Potential of olfactory neuroepithelial cells as a model to study schizophrenia: A focus on GPCRs (Review)

Sánchez‑Florentino,Zuly A.; Romero‑Martínez,Bianca S.; Flores‑Soto,Edgar; Serrano,Héctor; Montaño,Luis M.; Valdés‑Tovar,Marcela; Calixto,Eduardo; Aquino‑Gálvez,Arnoldo; López‑Riquelme,Germán O.; Alvarado,Ramón; Argueta,Jesús; Solís‑Chagoyán,Héctor; Sommer,Bettina

doi:10.3892/ijmm.2023.5331

Potential of olfactory neuroepithelial cells as a model to study schizophrenia: A focus on GPCRs (Review)

Authors:
- Zuly A. Sánchez‑Florentino
- Bianca S. Romero‑Martínez
- Edgar Flores‑Soto
- Héctor Serrano
- Luis M. Montaño
- Marcela Valdés‑Tovar
- Eduardo Calixto
- Arnoldo Aquino‑Gálvez
- Germán O. López‑Riquelme
- Ramón Alvarado
- Jesús Argueta
- Héctor Solís‑Chagoyán
- Bettina Sommer
View Affiliations

Affiliations: Neuropharmacology Laboratory, Clinical Research Branch, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City 14370, Mexico, Department of Pharmacology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico, Department of Health Sciences, Metropolitan Autonomous University Iztapalapa Unit, Mexico City 09340, Mexico, Department of Pharmacogenetics, Clinical Research Branch, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City 14370, Mexico, Department of Neurobiology, Neuroscience Research, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City 14370, Mexico, Molecular Biology Laboratory, Department of Pulmonary Fibrosis, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City 14080, Mexico, Socioneurobiology Laboratory, Center for Research in Cognitive Sciences, Autonomous University of The State of Morelos, Cuernavaca 62209, Mexico, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico, Department of Cognitive and Evolutionary Neuroscience, Center for Research in Cognitive Sciences, Autonomous University of The State of Morelos, Cuernavaca 62209, Mexico, Department of Research in Bronchial Hyperreactivity, National Institute of Respiratory Diseases Ismael Cosio Villegas, Mexico City 14080, Mexico
Published online on: November 28, 2023 https://doi.org/10.3892/ijmm.2023.5331
Article Number: 7
Copyright: © Sánchez‑Florentino et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in Disrupted‑in‑Schizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G protein‑coupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.

1. Introduction

Schizophrenia (SZ) is a multifactorial disease with an unspecified origin. Although genetic, environmental, psychosocial and other factors might be involved in its etiology, the precise pathophysiological mechanisms of its development remain unclear. SZ diagnosis is primarily based on symptoms classified as positive (hallucinations, delirium, disorganized speech, psychomotor disturbances), negative (affective flattening, alogia, avolition, asociality and anhedonia) or cognitive (memory and executive function deficits) (1,2).

SZ symptoms, specifically cognitive symptoms, are associated with the molecular structure of dopaminergic and serotonergic topology and brain networks (3).

A key objective in the study of neuropsychiatric disorders is to elucidate the pathophysiological processes occurring in the brain to improve understanding of the disease and diagnostic and therapeutic options available. The delicate nature of the brain complicates study, and although postmortem studies have yielded insight, there is need for suitable models to overcome ethical and methodological limitations to obtain brain samples. In recent years, in vitro models have emerged, such as the culture of induced pluripotent stem cells (iPSCs) (4) and induced neuronal (iN) cells (5), which allow reprogramming of cells into neural and glial cell lines (6). An alternative is the use of human olfactory neuroepithelial (hONE) cells: Primary neurons and glial cells can be taken via epithelial cells in the nasal cavity of living patients with a minimally invasive technique. The heterogeneous samples include stem cells with multipotent and regenerative capacities that can be differentiated into neuronal and glial cells for use in vitro and ex vivo (6,7). Neuropsychiatric disorders including SZ (8-12), Alzheimer's disease (13,14) and other mood and anxiety disorders (15) are associated with anosmia, and it has been shown that the olfactory epithelial cells of patients with these illnesses have cellular and molecular alterations, such as amyloid-β and paired helical filament-tau aggregates, alterations to the cell cycle and phosphatidylinositol signaling pathways, membrane phospholipid alterations, dysregulated neurodevelopmental pathways, dysregulated mitochondrial function, oxidative stress (16-25). Since the hONE cells of the olfactory bulb are connected to the olfactory cortex, neurobiological alterations in the limbic regions may be reflected in the hONE cells, suggesting these may serve as an appropriate model for the study of neuropsychiatric disorders.

In patients with SZ or SZ-like animal models, dysfunctions have been observed in intracellular mechanisms activated by key hormones, modulators and transmitters such as dopamine, glutamate, serotonin, acetylcholine (ACh), ATP, melatonin, endocannabinoids and oxytocin (26-28). These modulators exert action by binding to G protein-coupled receptors (GPCRs) and triggering complex downstream intracellular signaling cascades. In the physiology of the central nervous system (CNS), the GPCR family of receptors is involved in key cellular functions such as proliferation, differentiation, migration and neurotransmission both in undifferentiated and mature neurodevelopmental stages (29-31). Genomic and proteomic studies have demonstrated the association of SZ with alterations in expression of GPCRs and enzymes activated by them, such as phospholipase Cb (32-34). In addition, drugs (such as aripiprazole, azepine, chlorpromazine) used in the treatment of this psychiatric disorder target GPCRs. To the best of our knowledge, however, there are few studies of the functionality of these receptors and the actions of these drugs at the cellular level (6,35). One possibility to study these is the use of cells cultivated from patients.

The present study conducted a literature review on PubMed and Google Scholar, selecting articles associated with GPCRs and their connection to SZ, as well as GPCRs in stem cells and their relevance to SZ. The following search strategies were used: Schizophrenia AND olfactory epithelial cells AND GPCR; GPCR AND schizophrenia and schizophrenia AND stem cells.

2. Olfactory epithelial cells in in vitro study of SZ

To comply with the bioethical and anatomical restrictions around directly obtaining CNS tissue from patients with mental disorders or neurodegenerative diseases, several experimental approaches have been developed to study human neurons and neuroglial physiological processes at the cellular level (36-39). Cell models have been characterized, such as olfactory epithelial SCs, iP cells and monocytes induced to resemble neurons (6,21). In particular, SCs of the olfactory epithelium express different types of GPCR and may be a suitable model to study the function of these receptors at the cellular level and their alteration in SZ; alterations in neurodevelopment, stress response and gene/protein expression regulatory pathways have been found in patients with SZ through the use of cells in culture obtained from olfactory epithelium (40). Most of the currently validated cellular models take advantage of the specific characteristics of SCs, such as their self-renewal capacity and their differentiation potency (41,42). These characteristics are also useful to establish cryopreserved biobanks of neural SCs at different stages of development. These cells are multipotent and have been differentiated into neurons (43) and neuroglia (44), making the study of GPCRs at different stages of development in different cell types possible.

Studies have observed disease-associated pathological traits in both neural SCs and their differentiated progeny, such as alterations in microtubule organization (45), making these models suitable to investigate cellular and subcellular mechanisms underlying the pathophysiology of psychiatric disorder. Human olfactory neural stem cells obtained by the nasal cavity exfoliation procedure described by Benitez-King et al (37) have revealed cellular and subcellular alterations in patients with SZ, bipolar disorder and Alzheimer's disease (46) and in cannabis users (Fig. 1) (47,48). Specifically regarding GPCRs and their signaling, one study reported abnormal 3'-5'-cyclic adenosine monophosphate (cAMP) accumulation in patient-derived hONE cells (49). Another study reported melatonin MT1 and MT2 receptors and their involvement in the modulation of axonogenesis, associated with increased levels of phosphorylated (p)GSK3β (Fig. 1) (27); axonogenesis is impaired and melatonin receptor and pGSK3β levels are lower in cells derived from patients with SZ compared with those from healthy subjects (27). In olfactory cells of patients with SZ, trimethylation of histone H3 lysine and H3 lysine 27 alters expression of genes related to glutamate decarboxylase 1 and other pathways associated with SZ (50). Neural epithelial SCs from living patients obtained via non-invasive exfoliation allows observation of the pathophysiological mechanisms and structural and molecular changes in SZ (7,51,52). Moreover, this model presents an opportunity to obtain cells from a single patient at different stages of disease, including naive stages and during treatment. Numerous in vitro models for the study of SZ have been developed and standardized using other human biospecimens such as postmortem brains and genetically engineered cells due to their accessibility and reliability (37,40,53,54).

Figure 1

Olfactory neuroepithelial cells as a model to study schizophrenia at the cellular level. Mechanisms associated with schizophrenia at the cellular and molecular level, such as GPCR cellular signaling pathways, cellular functions, epigenetic markers, gene and protein expression; it also shows that neuroepithelial olfactory cells can be used as a pharmacological model. GPCR, G protein-coupled receptor.

Advantages and limitations of olfactory neuroepithelial cell models

The initial sample to develop iPSC and iN stem cells can be easily collected since, usually, peripheral cells are used. Meanwhile, the collection of hONE cells has moderate ease with a minimally invasive technique that a qualified professional should perform (6,55). hONE cells are ready for use ~4 weeks after collection, while iPSC require a longer waiting time (6). Additionally, costs to obtain hONE cells are lower than that for iPSCs and iN cells. hONE cells are neural tissue and do not require genomic reprogramming. Both hONE cells and iPSC have moderate or high proliferative capacity while iN cells do not possess this capacity (5,56). As iPSC and iN cells are induced models, it is difficult to determine the degree of phenotypical similarity with brain cells, while in hONE cells neurobiological properties are preserved (6). hONE cells are cultured from living patients, which allows the comparison of cells obtained at different stages of the illness and treatment.

GPCR involvement in SZ-related pathways using ONE cells

hONE cells are a relatively new model to study GPCR expression and function. hONE cultures have multipotent SC features and express functional purinergic P2 receptors (both ionotropic P2X and metabotropic P2Y receptors) (57). The activation of the purinergic pathway in these cells elicits transient increase in the intracellular calcium (Ca2+) concentration, mainly by the participation of the P2Y receptors; the calcium increase induces exocytotic processes in these cells (57).

Moreover, other functional GPCRs are expressed in human olfactory neural SCs, such as dopaminergic, serotoninergic and adrenergic receptors (ARs). These cells express markers of multipotency (Fig. 2A) and elicit an increase in intracellular Ca2+ concentrations in response to ligand binding (Fig. 2B). These characteristics contribute to a viable, minimally invasive model for neuronal culture sample from live patients with SZ to study the GPCR signaling pathways involved in this pathology.

Figure 2

Characterization of stem cells obtained from olfactory epithelium by detection of specific protein markers and functional evaluation. (A) Confocal image of an olfactory epithelial stem cell expressing SOX-2 (red) and neuron-specific human III β-tubulin (green). Nuclei are stained with DAPI (blue). (B) Intracellular Ca2+ concentration measurements illustrating the functionality of human olfactory epithelial stem cells. Stimulation with DA, 5-HT and or EPI increases intracellular Ca2+ concentration (unpublished material). DA, dopamine; 5-HT, serotonin; EPI, epinephrine.

3. Dysregulated calcium signaling in SZ

Ca2+ is a primary second messenger that regulates a myriad of cellular processes depending on its intracellular concentration, duration of stimulus and even global or local concentration changes (58).

The Ca2+ signaling system in neurons is responsible for the regulation of multiple neural functions, including exocytosis, neuronal excitability, control of brain rhythms, information processing and changes in synaptic plasticity involved in learning and memory (59). Dysregulation of the Ca2+ signaling pathway is implicated in the development of neural diseases, including SZ and bipolar disorder (59,60). Alterations in this system include the hypofunction of N-methyl-d-aspartate receptors (NMDAR) in early developmental stages, including complex transcriptional and compensatory events, resulting in a phenotypical switch in GABAergic neurons, altering γ rhythms (59). Even though the decreased activity of the NMDAR reduces Ca2+ flow, the overall effect causes an increase in intracellular Ca2+ in large neuronal populations (61,62). This is caused by the loss of inhibitory regulation in excitatory pathways from GABAergic interneurons (62,63). These pathways then increase intracellular Ca2+ by activating non-NMDA channels, including GPCRs (64). Furthermore, in the cerebral cortex of patients with SZ, elevated levels of calcium/calmodulin-dependent protein kinase II (CAMKIIIβ) have been observed (65); this enzyme promotes Ca2+-dependent neurotransmitter release (66,67) and this mechanism could be involved in the excessive dopamine release observed in animals dosed with amphetamine (68,69). Altered Ca2+ signaling in SZ could cause the reduced dendritic extension and branching observed in prefrontal cortical neurons (70,71), since an optimal balance is required to maintain dendritic trees and altered Ca2+ concentration can cause dendritic deformations (72-74). An increase in Ca2+ activates cell apoptosis and may be associated with decreased neuronal cell number in cortical and subcortical regions observed in patients with SZ (75-80). Additionally, patients with SZ present an abnormal increase in neurons in the cortical white matter (81), and this may be caused by Ca2+ dysregulation affecting neuronal migration (82,83). To the best of our knowledge, however, the participation of GPCRs in Ca2+ signaling has not been investigated in hONE cells.

4. Role of GPCRs in cellular signaling in SZ

SZ clinical onset usually happens in early adulthood. It occurs in ~1% of the human population and in the US it is estimated to decrease lifespan by 28.5 years (84). Patients with SZ present brain structural alterations as well as dysfunction in several neurotransmission systems (dopaminergic, glutamatergic, GABAergic, ACh and serotonergic signaling), in addition to inflammation and oxidative stress. Patients also present loss of cerebral gray matter and abnormal distribution of neurons in the prefrontal cortex (PFC) (85-87). Patients with SZ present structural alterations in heavily myelinated brain tracts that comprise mostly white matter, which suggests that impaired brain connectivity and an overall dysfunction of the axo-myelin unit is a key mechanism underlying the pathophysiology of SZ (88). SZ has a complex genetic background and development depends on environmental factors (89,90). GPCRs play a key role in the development, progression and treatment of SZ (Table I).

Table I

GPCR alterations identified in animal models, ex vivo assays and patients with SZ.

Dopaminergic receptors

The biological functions of the catecholaminergic neurotransmitter dopamine in the brain and periphery are mediated by dopamine receptors D1-5. These functions include regulation of sleep, feeding, synaptic regulation, attention, cognitive function, hormonal regulation, affection, reward systems, voluntary movement, vision and smell (91).

Based on binding to G proteins, dopamine receptors are classified as class 1 (D1 and D5) or 2 (D2, D3 and D4). D1-type receptors are mainly associated with Gαq/Gs proteins and stimulate adenylyl cyclase (AC) activity, cAMP production and Ca2+ release from intracellular stores. By contrast, D2-type receptors bind with Gα i/o proteins to inhibit cAMP production (92,93). Dopamine receptors are the most studied molecular targets in numerous neurological and psychiatric disorders, such as SZ, Parkinson's disease, bipolar disorder, attention deficit hyperactivity disorder, Huntington's disease, and Tourette syndrome (94-96). The exacerbation of the psychotic effects of dopaminergic drugs in SZ may be due to excessive stimulation of supersensitive postsynaptic dopaminergic receptors, particularly D2 receptors, which is the pharmacological target of antipsychotics (97).

Variation in dopamine levels and the symptoms of SZ are dependent on the associated brain region; increased release in the striatum is associated with positive symptoms (hallucinations and delusions) where the binding of the D2 receptor predicts the response to treatment with antipsychotics. However, the occupation of D2 receptors in the ventral region of the striatum is associated with negative symptoms such as passivity, apathy and social withdrawal (98). These conclusions are supported by genetic research showing a clear association between the dopamine receptor D2 gene and SZ (86,99). Although the majority of the currently authorized antipsychotic drugs block D2-type dopamine receptors, clinical symptomology is not completely treated in most patients. However, they have effects on other receptors in the brain, such as dopamine, serotonin, histamine, norepinephrine and ACh receptors, resulting in other abnormality, such as the risk of extrapyramidal side effects (100). D2 receptors are involved in postsynaptic activation and autoreceptor-mediated inhibition of dopamine release in the striatum and the D1 receptor modulates actions of dopamine in the corticostriatal circuitry; alterations in dopamine D1 receptors and key molecules in their signaling pathways have been found in the PFC of patients with SZ (101). Other studies have visualized expression in limbic and cortical areas of D3 and D4 dopamine receptors (102,103). Moreover, clozapine, a second generation antipsychotic drug, has a higher affinity for the D4 receptor, which supports its participation in the pathophysiology of SZ (102). On the other hand, the distribution and low cerebral abundance of D3 receptors, as well as their close homology with the D2 receptor, indicate they may serve as pharmacological targets, especially since their implementation could avoid the adverse motor effects produced by the inhibition of the D2 receptor (104).

ARs

ARs are divided into α1, α2, β1, β2, and β3. The α1 receptors couple to protein Gq/phospholipase C signaling proteins and α2 couple to Gi proteins. The β1 and β2 adrenoceptors activate Gs/AC/cAMP/protein kinase a (PKA) and β3 receptors couple to both Gs and Gi (105).

α1-ARs present three molecular subtypes (α1A, α1B, and α1D) that regulate the functions of the sympathetic nervous system by transducing signals after binding with cognate agonists, such as endogenous catecholamines norepinephrine and epinephrine (106). In the peripheral nervous system (PNS), α1-ARs participate in nervous regulation of the cardiovascular and other system functions (107).

The positive symptoms of SZ are exacerbated by selective and indirect AR agonists (ephedrine, clonidine and desipramine), while they are decreased by antagonists (yohimbine, propranolol and oxypertine) (85,108). Additionally, α-ARs are linked to cognitive deficit in SZ (109) and PFC impairment via PKC activation (85,110,111). In neocortical pyramidal cells, adrenergic arousal controls coupling between apical and somatic integration regions by the regulation of hyperpolarization-activated currents (Ih) and altering apical amplification (AA) (112). Higher levels of cAMP lead to excessive Ih, therefore increasing AA. Patients with SZ exhibit translocation in the disrupted in schizophrenia 1 (DISC1) gene and DISC1-regulated phosphodiesterase 4 (PDE4) activity; in the presence of high concentration of cAMP, this increases hydrolysis; however, but this process is altered in these patients (113,114). This area is key for spatial working memory (WM), in which α2A receptors serve a key role by inhibiting the cAMP/PKA pathway, thus reducing the persistent firing by increasing the open state of hyperpolarization and cyclic nucleotide-gated channels (115,116). The effects of adrenergic signaling are subtype-specific and could be influenced by noradrenaline concentration and receptor affinity. The effect is mediated through the persistent firing of the α2A receptors, and the use of an exogenous general β agonist does not alter the outcome. This phenomenon may be related to the upregulation of cAMP (117). In another study, the use of a β1 antagonist improved WM and the activation of β2 enhanced this effect, illustrating the complex modulation by adrenergic receptors (117-119).

Certain single nucleotide polymorphisms (SNPs) have been associated with SZ, including two SNPs in the promoter region of the α1A receptor gene (120), as well as methylenetetrahydrofolate reductase (MTHFR) (121,122). A detection system has been proposed to measure levels of 5-MTHF in patients with MTHFR SNPs (123).

Muscarinic receptors

ACh is a crucial neurotransmitter that participates both in the CNS and PNS. There are two types of receptors activated by ACh, nicotinic ionotropic and muscarinic metabotropic receptors (mAChRs) (124). There are five types of muscarinic receptors that can be classified as those coupled to Gq/G11 (M1, -3 and -5) and those coupled to Gi/o (M2 and -4) (124-126). The M1 receptor is the most prevalent receptor in the CNS, located in postsynaptic neurons and some peripheral tissues (126). Meanwhile, in the presynaptic neurons, the M2 and M4 receptors are expressed, while in the postsynaptic neurons, the M3, M4 and M5 receptors are expressed, with the M3 typically being the less abundant (126). Lower levels of M1 and M4 expression have been detected in the cortex (127,128), hippocampus (129) and striatum (130).

Genetic alterations in the muscarinic signaling pathway have been associated with SZ, including SNPs in the gene for the muscarinic acetylcholine receptor M1 (CHRM1) (131), as well as changes in methylation of the promoter of this gene, caused by the increase in microRNA (miRNA or miR) that regulates this gene (miR-107) (132). SNPs for CHRM4 (126,133) and CHRM5 (126,134) have also been linked with an increased risk of SZ.

The use of animal models has demonstrated the participation of the mAChRs in the pathogenesis of SZ. In M1 knock-out (KO) mice, impaired WM and long-term potentiation are observed (126,135). In a double KO mice model for M1 and M4, impaired prepulse inhibition (PPI) is observed (126,136). M4 KO mice models have been reported to present impaired PPI, abnormal social behavior, locomotor activity, sensorimotor gating, abnormal antipsychotic function, dopaminergic hyperexcitability and altered striatal dopamine release regulation (126,137-142). It has been observed that M5 KO mice present changes in PPI and reduced striatal dopamine release (126,142-144).

Alterations in other participants of this signaling pathway affect SZ. Acetylcholinesterase inhibitors, the enzyme that hydrolyses ACh, decrease visual hallucinations (85,145,146). Additionally, choline acetyltransferase (ChAt), the enzyme that synthesizes Ach, has decreased activity in the nucleus accumbens and pontine tegmentum of patients with SZ, which is associated with cognitive performance. An SNP for ChAt is associated with SZ (147).

Glutamatergic receptors

Glutamate is the primary excitatory neurotransmitter in the CNS responsible for modulation of synaptic transmission and neuronal excitability. This modulation is mediated by the activity of ionotropic and metabotropic glutamate receptors (mGluRs) (85,148,149). There are eight subtypes of mGluRs encoded by the glutamate metabotropic receptor 1 (GRM1)-8 genes and these receptors are be classified into three groups: Group I includes receptors coupled to a Gq/11 protein (mGluR1 and mGluR5) and group II (mGluR2 and mGluR3) and III (mGluR4, -6, -7 and -8) are coupled to Gi/Go protein (85,148,149). All receptor subtypes are expressed in neurons and glial cells, except mGluR6, which is primarily expressed in the retina (85,150).

Alterations in mGluR1 are associated with SZ. Patients with SZ may have deleterious GRM1 non-synonymous SNPs (85,151); in postmortem studies, patients with SZ have higher levels of mGluR1α in the PFC (85,152). The role of mGluR1 has been studied through KO mice. These animals have decreased hippocampal long-term potentiation leading to a deficit in associative learning (148,153,154) and activity-dependent synaptic plasticity (154). mGluR1 deficiency causes long-term depression in the cerebellum and motor learning impairment (148,155) and a decrease in PPI (148,156). Use of mGluR1 negative allosteric modulators is effective in the treatment of positive SZ symptom models (85,148,157).

mGluR5 may be involved in SZ as this receptor potentiates the NMDAR in brain regions of interest in SZ (158). In mGluR5KO mice, there is a deficit in PPI (148,159). Furthermore, a KO model of miR-50103p induces dendritic structural defects, glutamatergic transmission enhancement and sociability, memory and sensorimotor gating deficits, which are attenuated when restoring miR-50103p expression. These effects were attributed to the upregulation of mGluR5 since this miRNA negatively regulates the expression of the receptor. When using a negative allosteric modulator of mGluR5, similar effects were observed (160). In animal models of positive and negative symptoms, a positive allosteric modulator of mGluR5 effectively improves all types of SZ symptom (85,148,157). Furthermore, mGluR5-selective negative allosteric modulators in adult rats causes social interaction deficits, impaired WM, reduced instrumental learning, decreased overall response in 5-choice serial reaction time task (5-CSRT) and increased NMDAR antagonist side effects (158,161-165). Postsynaptic mGluR2/3 activation can augment NMDAR currents via Src kinase in pyramidal cells of the hippocampal CA1 (166) and in the PFC via PKC activity (167) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins (157,168).

Although the group II receptors have not been as extensively studied, they may serve as therapeutic targets. In animal models of SZ, the activation of mGluR2/3 decreases the psychomotor activity and neurochemical effects produced by psychostimulants (85,169). Agonists of mGluR2/3 decrease extracellular dopamine efflux in the substantia nigra, nucleus accumbens and dorsal striatum (157,170-173). The activation of mGluR2/3 functions as an autoregulator to decrease glutamate release, makes it a target for the development of agonists for treatment of SZ (157,174). Additionally, in preclinical trials, mGluR2/3 agonists (LY354740 and LY379268) decrease NMDAR antagonist-induced hyperlocomotion (175-178) and behavioral stereotypes (175,179) and behavioral and electrophysiological effects and head twitches induced by (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice (180) and improve SZ-like symptoms induced by prenatal stress and postnatal isolation (157,181,182). In negative symptom models, the agonists improve deficits in social interaction (183-185) and mobility attenuated by dizocilpine in the swimming test (157,178). For cognitive symptoms, mGluR2/3 agonists decrease deficits in discrete-trial delayed alternation task (175) and errors in the 5-CSRT (157,186). However, it has also been shown that agonists can impair cognitive symptoms. Impaired cognition by inhibiting hippocampal synaptic transmission (187) and exacerbated deficits in the 5-CSRT have been observed (157,188).

mGluR2 is associated with the serotonergic receptor 5-HT2AR based on the behavioral, pharmacological, and biochemical results observed when antagonizing receptor signaling (157,189-191). The antipsychotic properties of mGluR2 have been attributed to the effects on the serotonin receptor and it has also been observed that 5-HT2AR antagonism in mice with atypical antipsychotics decreases expression of GRM2 encoding mGlu2 through a decrease in histone deacetylase 2 (157,192).

The least explored receptors are those in group III. All receptors in this group have been studied in KO mice models (180,184-197). The administration of a group III agon ist (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACTP-1) decreases hyperlocomotion induced by MK-801 and amphetamines and improves head twitches induced by DOI in mice (157,193). The mGluR4 is expressed throughout the brain but is most densely expressed in the cerebellum; KO mice can present impairments in cerebellar synaptic plasticity and motor learning of complicated tasks and altered spatial memory performance. These receptors are key in regulation of GABAergic absence seizures in the thalamocortical region (148,194-196). In positive symptom animal models, the administration of mGluR4 agonist (LSP1-2111 and LSP4-2022) improves psychosis symptoms (hyperlocomotion and head twitches) (157,197,198). mGluR4 agonists also improve deficits in social interaction and novel object recognition (157,198). mGluR6, which is primarily expressed in the retina, presents delayed response when retinal bipolar cells are stimulated with light in mGluR6 KO mice (148,199,200). There have been reports of photoreceptor and bipolar and retinal ganglion cell (RGC) dysfunction in SZ (201,202). RGC signaling deficit is associated with SZ, particularly in patients that experience visual hallucinations (202).

The mGluR7 receptor is widely expressed but has a lower affinity to glutamate than other receptors and downregulates overstimulation by glutamate (148), as indicated by the epileptic phenotype observed in mGluR7 KO mice (148,203). mGluR7 KO mice exhibit worse short-term neural plasticity in the hippocampus (85,204,205), memory and learning deficits (204,206-209) and an altered fear (209) and anxiety response (20,85,148,204,210). In preclinical studies, mGluR7 negative allosteric modulators 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c] pyridin-4(5H)-one and (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one improves symptoms caused by MK-801 and DOI-induced head twitches (85,211-213), while an mGuR7 agonist (AMN082) produces the opposite effects (157,197).

mGluR8 is less expressed than mGluR4 and -7; it is primarily expressed presynaptically and widely throughout the brain (148,157). This receptor serves as an autoreceptor in the lateral prefrontal path of the dentate gyrus, therefore gating glutamatergic transmission into the hippocampus (157,214), which is why mGluR8 KO mice exhibit deficiency in hippocampal-mediated learning (157,215). Unlike the other group III receptors, mGluR8 agonist [(S)-3,4-DCP] does not affect NMDAR or amphetamine hyperactivity, suggesting that it might be an ineffective target for SZ treatment (157,216).

Purinergic receptors

P2Y metabotropic purinoceptors are a family of proteins divided into eight subtypes (P2Y1, 2, 4, 6 and 11-14) that can be activated by several nucleotides such as ATP, ADP, UTP, UDP and UDP-glucose (217). Activation of these receptors induces biological effects due to the subsequent activation of different effectors, including MAPK, ρ-associated protein kinase, phospholipase A2, nitric oxide and the transactivation of growth receptors (218). Several signaling pathways activated by ATP and other nucleotides via P2Y, participate in regulation of CNS development. Stimulation of the P2Y1 receptor promotes adult neurogenesis (219,220). The P2Y receptors have been suggested to be involved in SZ. P2Y1 receptor agonist (MRS2365) to the PFC in rats impairs WM and other behavioral responses that may be involved in conditions that increase ATP concentration, such as SZ (221). Perisomatic interneurons, which modulate γ oscillations, express P2Y1Rs (222). These cells have been implicated in SZ and cognitive deficit (222) and γ oscillations and PPI alterations have been reported in SZ animal models (223,224).

The role of the purinergic signaling system in SZ has gained interest (225,226). Based on modulation of glutamatergic and dopaminergic systems by adenosine, it has been theorized that complications during the early stages of brain development lead to an excessive release of adenosine that induces brain changes. The dysfunctional activation of adenosine receptor A1R decreases activity of dopamine, consequently increasing cytotoxicity through glutamate (227). Adenosine A2A receptor (A2AR) KO mice showed that, in astrocytes, these receptors disrupt glutamate homeostasis, leading to psychomotor and cognitive impairment, which may be involved in the development of SZ (228). Moreover, A2ARs can form heterodimers with D2 receptors. A2ARs are highly expressed in certain brain regions implicated in SZ and may modulate D2 receptors. However, no difference in expression of these receptors is observed in male patients with SZ treated with antipsychotic medication compared with healthy controls by measuring a tracer through positron emission tomography (229).

Wnt/FRIZZLED (FZD) receptors

Wnts transduce signaling cascades to regulate SC differentiation in various types of tissues such as skin, muscle, colon and bone marrow; in addition, they promote cell proliferation and differentiation to regulate maintenance of the adult hippocampus and neuronal progenitors of the subventricular zone (230,231). A distinctive aspect of Wnt signaling is its ability to favor tissue growth while inducing cell proliferation, serving as a directional growth factor and preventing the formation of amorphous structures, an essential feature during tissue development and homeostasis in adults (232,233).

Neuroinflammation and immune dysfunction could be involved in the pathogenesis of SZ, supported by the higher incidence of autoimmune disease in patients with SZ. The inflammatory process is mediated by Wnt/β-catenin dysregulation, with the primary effector being NF-κB, stimulating production of inflammatory markers, including various cytokines, and favoring oxidative stress. Many of these processes promote psychotic symptoms. SZ is associated with a decrease in Wnt/β-catenin pathway activity, leading to an upregulation of PPARγ and downregulation of PPARα (234-236). The increase of PPARγ increases oxidative stress and inflammation (234). The Wnt/β-catenin pathway is involved in the pathogenesis of numerous neuropsychiatric disorders. There have been reports of myelin and oligodendrocyte dysfunction in SZ (88,237), indicating that the Wnt/β-catenin pathway could be altered in this illness. The levels of β-catenin are decreased in the hippocampal region of patients with SZ and downstream alterations in this pathway have been also observed (238).

Genome-wide SNP analysis has identified multiple SNPs associated with SZ, including the FZD1 gene at chromosome 7q21.13 (239), as well as FZD3 gene on the chromosome 8p21 (240-242). FZD3 SNPS are also implicated in methamphetamine psychosis (243). There is aberrant Wnt gene expression at multiple levels of the signaling pathway. Microarray analysis demonstrates that patients with SZ exhibit dysregulated mRNA expression of genes that attenuate β-catenin signaling and favor non-canonical signaling, while transcription factor nuclear factor of activated T cells 3, which is activated downstream by the non-canonical pathway, is upregulated (244).

Cannabinoid receptors

Cannabinoid receptor subtypes 1 and 2 (CB1 and CB2) are metabotropic receptors primarily coupled to Gi/o proteins. Activation of these receptors inhibits the enzymatic activity of AC), and decreases the intracellular levels of cAMP (245). These receptors couple to Gq/11 or Gs, inducing different responses (246). They are expressed in neuroglia, immune cells and neurons in the CNS (247). Furthermore, olfactory (248) and neural SCs (NSCs) express a functional endocannabinoid system (249).

CB2 receptors are usually absent in neurons, although they are functionally active in SCs and, together with CB1, modulate processes such as proliferation, cell cycle maintenance, and NSC differentiation via the PI3K/Akt pathway (250-253).

Excessive activation of the endocannabinoid system through CB1 receptors of inhibitory GABAergic interneurons in the ventral tegmental area, basolateral amygdala and the medial PFC generates a hyperdopaminergic and hypoglutamatergic environment, causing SZ (254,255). Through in vivo and postmortem studies, it has been shown that gene, mRNA and protein levels of these receptors are decreased and dysregulated in multiple brain regions of patients with SZ (256-258). In animal models, chronic blockade of CB2 receptors has been shown to induce anxiolytic action (259). Treatment with a selective CB2 agonist reduces depressive-like behaviors (260). Maternal deprivation induces a significant increase in CB2 receptor immunoreactivity in the hippocampus, suggesting participation of this receptor in psychiatric neurodevelopmental diseases such as SZ (261). Polymorphisms in the genes for cannabinoid receptors and the endocannabinoid system are associated with SZ (28) and quality of the response to antipsychotics (262).

Sphingosine-1-phosphate (S1P) receptors

S1P is produced in all cell types during the catabolic degradation of membrane glycosphingolipids and sphingomyelin, which results in sphingosine that is phosphorylated by sphingosine kinase (SphK) to S1P, a bioactive signaling molecule that serves as a ligand for GPCRs of the Gi/o, G12/13, and Gq types (263). Various hormones, cytokines and growth factors can activate the SphK/S1P signaling pathway, modulating cell proliferation, migration and survival. The SphK/S1P pathway has been associated with stem/progenitor cells and tissue self-renewal in the vascular, immune, muscular and nervous systems (264-267).

In the pathogenesis of SZ, there are alterations in myelin, white matter integrity and metabolism of lipids. Recent targeted mass spectrometry-based analysis found that postmortem samples of the corpus callosum of patients with SZ have lower levels of S1P (268). Furthermore, one study divided patients with SZ into those that present an upregulation of S1PR1 and those that have levels comparable to controls (269). This may be used as a biomarker since S1PR1 can be detected through positron emission tomography (269).

Neuropeptide Y (NPY) receptors

NPY is a 36-amino acid peptide produced by GABAergic interneurons that is widely expressed in the CNS and PNS during development and adulthood. The Y receptors are a family of proteins divided into five subtypes (Y1, Y2, Y4, Y5, and Y6) that are activated by the NPY family of hormones, which consists of three native peptide ligands (NPY, pancreatic polypeptide and peptide YY). All NPY receptors are involved in the Gi signaling cascade; upon activation, the α subunit decreases cAMP production and the b/g subunit activates various kinase cascades. This ligand-receptor interaction can lead to decreased Ca2+ channel activity and increased G-protein-coupled inward rectifying potassium currents (270,271).

NPY serves an important role in the regulation of learning, memory, feeding and endocrine secretion (272). NPY is found in the olfactory neuroepithelium, where it stimulates proliferation of olfactory SCs (273). Additionally, NPY regulates the response of olfactory receptors, apoptosis and cell regeneration (274) and protects sensory neurons from death due to excessive GluR activation by decreasing Ca2+ entry into the presynaptic nerve terminal via PKA- and p38K-associated signaling (275).

NPY participates in adult neurogenesis in the hippocampal dentate gyrus, caudal subventricular zone and subcallosal zone (276). In vivo, by fusing NPY vectors with a brain transport peptide (apolipoprotein B), proliferation of neural precursor cells in the subgranular zone of the hippocampus increases substantially without neuronal differentiation (277). Furthermore, NPY promotes the proliferation of olfactory and hippocampal SCs (272,273,278).

NPY gene and mRNA expression is decreased in PFC of patients with SZ (279,280); these prefrontal deficits depend on regional supply of brain-derived neurotrophic factor through a miRNA-regulated mechanism (279). Additionally, activation of the Y2 subtype of NPY receptor regulates central dopamine signaling, which is closely related to the pathophysiology of psychotic symptoms (281,282).

Chemokine receptors

Chemokines are a family of small cytokines (CXC, CC or β-chemokines, C, and CX3C), that regulate chemotaxis, hematopoiesis, angiogenesis, survival, proliferation, migration and degranulation of leukocytes by coupling with their respective GPCRs (283). Chemokine receptors are divided into four subtypes according to their activating chemokine ligands (284). Chemokines are key regulators of SCs in specific tissues (268,285) and can mediate migration of multipotent SCs (286). CXCR4 modulates growth factor signaling and is expressed in vitro in adult human and murine NSCs and cells from the embryonic murine subventricular zone (287).

In addition to chemotactic functions, it has been observed that chemokines participate in neuromodulation, neurotransmission and neurogenesis, exert a pleiotropic effect and exacerbate inflammation, which is why their dysregulation is associated with neurobiological processes associated with mental illnesses such as SZ (284,288). A systematic review demonstrated an association between chemokines and neuroinflammation and the pathogenesis of SZ, highlighting that there is a genetic association of SZ with polymorphisms of chemokine receptor genes, blood levels of CXCL8/IL-8, CCL2/(monocyte chemoattractant protein 1, chemokine (C-C motif) ligands 4 (CCL4)/macrophage inflammatory protein 1β (MIP-1β), and CCL11/eotaxin-1 are increased and chemokine expression and their receptors are changed in brain regions and peripheral immune cells of patients with SZ and animal models have revealed molecular mechanisms associated with deregulation of the CX3CL1-CX3CR1 and CXCL12-CXCR4 axes, demonstrating that deregulation of chemokine expression may contribute to the neurobiological processes that cause SZ (284).

5. GPCRs as therapeutic targets in SZ

Management of patients with SZ consists of pharmacotherapy and/or psychotherapy and its principal goal is to improve quality of life and limiting side effects of treatment to maintain adherence to the treatment. The primary pharmacological therapy used in SZ is based on total or partial antagonists of the dopamine D2 receptor, however, few patients fully recover or exhibit reversed negative symptoms (Table II). Moreover, the cognitive impairments of SZ are usually resistant to current antipsychotic treatment (289).

Table II

Effect of different agonistic and antagonistic treatments targeting GPCRs in patients with schizophrenia.

Table II

Effect of different agonistic and antagonistic treatments targeting GPCRs in patients with schizophrenia.

Drug	Typical GPCR-associated signaling	Atypical GPCR-associated signaling
Aripiprazole	Dopamine Antagonist (√√√) D₂ G_i ↓cAMP ↓Ca²⁺ ↓IK⁺; (√√) D₃ G_i ↓ cAMP; (√) D₄G_i ↓cAMP ↓Ca²⁺ ↓IK⁺	Serotonin Antagonist (√√√) 5HT_1a G_s cAMP; (√√√) 5HT_2a Ca²⁺ PLC; (Ö) 5HT_2c Ca²⁺ PLC; (√) 5HT₇ G_s↑ cAMP Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺ Histamine Antagonist (√) H₁ G_q IP₃/Ca²⁺
Azepine	Dopamine Antagonist (ÖÖÖ) D₂ G_i ↓cAMP ↓Ca²⁺ ↓IK⁺; (√) D₃ G_i ⁻cAMP	Serotonin Antagonist (√√√√) 5HT Ca²⁺ 2a PLC; (√√) 5HT_1a Gs ↑cAMP; (√√) 5HT_1b G_i ↓cAMP; (√√) 5HT_2c Ca²⁺ PLC; (√) 5HT₆ G_s ↑cAMP; (√) 5HT₇ G_s ↑Camp
Chlorpromazine	Dopamine Antagonist (√√√) D₁ G_s ↑cAMP; (√√) D₅ G_s ↑ cAMP; (Ö) D₂ G_i ↓cAMP ↓Ca²⁺ ⁻IK⁺; (√) D₃ G_i ↓cAMP	Serotonin Antagonist (√√√) 5HT1a G_s ↑cAMP; (√√√) 5HT_2a Ca²⁺ PLC Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺; (√√) a2 G_i ↓cAMP Histamine Antagonist (√) H₁ G_q IP₃/Ca²⁺ Muscarinic Antagonist (√) M₁ G_q IP₃/Ca²⁺; (√) M₂ G_i ↓cAMP ⁻IK⁺
Clozapine	Dopamine Antagonist (√√√) D₁ G_s cAMP; (√√) D₄ G_i ↑ cAMP ;(Ö) D₂ G_i ↓ cAMP ↓ Ca²⁺ ↓IK⁺; (√) D₃ G_i ↓ cAMP	Serotonin Antagonist (√√√) 5HT_2a Ca²⁺ PLC Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺ Muscarinic Antagonist (√√) M₁ G_q IP₃/Ca²⁺; (√) M₂ G_i ↓cAMP ⁻IK+; (√) M₃ G_q IP3/Ca²⁺ Muscarinic Agonist (√) M₄ G_i ↓cAMP ↓IK⁺
Fluphenazine	Dopamine Antagonist (√√√) D₂ G_i ↓cAMP ↓Ca²⁺ ↓IK⁺	Muscarinic Antagonist (√√) M₁ G_q IP₃/Ca²⁺ Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺ Histamine Antagonist (√) H₁ G_q IP₃/Ca²⁺
Haloperidol	Dopamine Antagonist (√√√) D₁ G_s ↑ cAMP; (√√) D₂ G_i ↓cAMP ⁻Ca²⁺ ↓IK⁺	Muscarinic Antagonist (√) M₁ G_q IP₃/Ca²⁺ Adrenergic Antagonist (√) a1 G_q IP₃/Ca²⁺
Olanzapine	Dopamine Antagonist (√√√) D₁ G_s ↑ cAMP; (√√) D₅ G_s ↑ cAMP; (√√) D₂ G_i ↓cAMP ⁻Ca²⁺ ↓IK⁺; (√) D₃ G_i ↓cAMP	Serotonin Antagonist (√√√) 5HT Ca²⁺ 2a PLC; (√√√) 5HT_2c Ca²⁺ PLC Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺ Muscarinic Antagonist (√√) M₁ G_q IP₃/Ca²⁺; (√) M₂ G_i ↓ cAMP ↓IK⁺; (√) M₃ G_q IP₃/Ca²⁺; (√) M₄ G_i ↓cAMP ⁻IK⁺; (√) M₅ G_q IP₃/Ca²⁺ Histamine Antagonist (√) H₁ G_q IP₃/Ca²⁺
Quetiapine	Dopamine Antagonist (√√) D₁ G_s ↑ cAMP; (√√) D₂ G_i ↓cAMP ↓Ca²⁺ ↓IK⁺	Serotonin Antagonist (√√√) 5HT₂ Ca²⁺ PLC; (√√√) 5HT₁ G_i ↓cAMP ⁻IK⁺ Histamine Antagonist (√) H₁ G_q IP₃/Ca²⁺ Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺; (√) a2 Gi ↓ cAMP
Perphenazine	Dopamine Antagonist (√√) D₂ G_i ↓cAMP ↓Ca²⁺ ↓IK⁺	Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺
Risperidone	Dopamine Antagonist (√√) D₂ G_i ↓cAMP ↓Ca^{2+ −}IK⁺; (√) D₃ G_i ↓ cAMP	Serotonin Antagonist (√√√) 5HT₂ Ca²⁺ PLC Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺ Histamine Antagonist (√) H₁ G_q IP₃/Ca²⁺ Muscarinic Antagonist (√√) M₁ G_q IP₃/Ca²⁺; (√√) M₂ Gi ↓cAMP ⁻IK⁺
Thioridazine	Dopamine Antagonist (√√) D₂ G_i ⁻cAMP ↓Ca²⁺ ↓IK⁺	Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺
Trifluoperazine	Dopamine Antagonist (√√) D₂ G_i ↓cAMP ↓Ca²⁺ ↓IK⁺	Adrenergic Antagonist (√√) a1 G_q IP₃/Ca²⁺
Ziprasidone	Dopamine Antagonist (√√) D₂ G_i ↓cAMP ↓Ca²⁺ ↓IK⁺ ; (√) D₃ G_i ↓cAMP	Serotonin Antagonist (√√√) 5HT Ca²⁺ 2a PLC; (√√) 5HT Ca²⁺ 2c PLC; (√√) 5HT_1d G_i ↓cAMP ↓Ca²⁺ ↓IK⁺ Adrenergic Antagonist (√) a1 G_q IP₃/Ca²⁺ Histamine Antagonist (√) H₁ G_q IP₃/Ca²⁺

[i] (√√√) High effect; (√√) Moderate effect; (√) Mild effect; ↓ decreased effect; ↑ increased effect. The information of this table was taken from (2,292,303). GPCR, G protein-coupled receptor; IK, potassium current; 5-HT, serotonin; PLC, phospholipase C; IP₃, inositol 1,4,5-trisphosphate; Gi, G inhibitory; Gs, G stimulatory.

GPCRs play an important role in the treatment of SZ because they transmit the extracellular signal into cells by activating the signaling cascade coupled to G proteins. Advances in pharmacology have made it possible to identify drugs that can modify the interaction of GPCRs related to dopaminergic and serotonergic activity in the treatment and management of SZ (290,291). Understanding the role of GPCRs in the signal transduction of SZ is fundamental for the discovery of pharmacological targets. The basis of pharmacological treatment for SZ requires a complete understanding of GPCR-mediated signaling, transducers and associated second messengers. Structural plasticity of GPCR proteins underlying physiological regulation with pharmacological implications in clinical use has been summarized previously (292).

Considering SZ pathophysiology and ineffective antipsychotic therapy with severe side effects and poor adherence to the therapeutic regimen that diminishes quality of life and undermines the beneficial effects of the drugs, novel treatments directed at the whole symptomatology as well as specific symptoms are needed. There are numerous clinical studies of GPCR targets, including those directed at general, positive, negative and cognitive symptoms (30,293,294).

6. Conclusion

The present review demonstrated that GPCR alterations can be associated with the pathophysiology of psychiatric disorders and neurodegenerative diseases, such as SZ. GPCRs are a therapeutic target of antipsychotics used in the treatment of SZ. To the best of our knowledge, however, experimental evidence regarding the functionality of these receptors in patients is scarce. Knowledge of GPCR signaling in human multipotent SCs and their progeny differentiated in neurons or neuroglia could widen the study of the pathophysiology of SZ and other diseases such as diabetes, myocardial infarction, stroke, Parkinson's disease, Alzheimer's disease and multiple sclerosis.

Some of the limitations of hONE as a model of study in SZ include lack of information about GPCRs functionality in hONE cells; also, since these cells are undifferentiated, they may have a distinct expression of channels and receptors than their differentiated progeny, and the results obtained in the undifferentiated cells should be corroborated in conventional SZ models based on differentiated dopaminergic and serotoninergic neurons.

Models such as patient-derived iPSCs, transdifferentiated neurons, olfactory sensory neurons and cerebral organoids can provide understanding of SZ and facilitate the development of treatment. Particularly, the culture and cryopreservation of olfactory SCs have been characterized and used to identify several dysfunctional processes at a cellular level; this has been proposed as a model to understand the pathophysiology of neuropsychiatric disorders and detect biomarkers for diagnosis. This model could be useful to study the functionality of GPCR in SZ. GPCRs and their associated signaling pathways are possible therapeutic targets for SZ, although further research using experimental and bioinformatic tools is needed.

Availability of data and materials

Not applicable.

Authors' contributions

ZASF, BSRM, EFS, BS and HSC conceived the study. HS, LMM, MVT, EC, AAG, GOLR, RA and JA edited the manuscript. All authors wrote the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

The authors would also like to thank Ms Maria del Pilar Romo and Ms Rosalba Linares for administrative and technical support (National Autonomous University of Mexico, Mexico City 04510).

Funding

The present study was supported by Consejo Nacional de Humanidades Ciencia y Tecnología (grant no. CF/2019/137725) and Programa Presupuestario F003 (grant no. 287115).

References

1	Tandon R, Gaebel W, Barch DM, Bustillo J, Gur RE, Heckers S, Malaspina D, Owen MJ, Schultz S, Tsuang M, et al: Definition and description of schizophrenia in the DSM-5. Schizophr Res. 150:3–10. 2013.
2	Gaebel W and Zielasek J: Schizophrenia in 2020: Trends in diagnosis and therapy. Psychiatry Clin Neurosci. 69:661–673. 2015.
3	Chen J, Müller VI, Dukart J, Hoffstaedter F, Baker JT, Holmes AJ, Vatansever D, Nickl-Jockschat T, Liu X, Derntl B, et al: Intrinsic Connectivity Patterns of Task-defined brain networks allow individual prediction of cognitive symptom dimension of schizophrenia and are linked to molecular architecture. Biol Psychiatry. 89:308–319. 2021.
4	Marchetto MC, Brennand KJ, Boyer LF and Gage FH: Induced pluripotent stem cells (iPSCs) and neurological disease modeling: Progress and promises. Hum Mol Genet. 20:R109–R115. 2011.
5	Yang N, Ng YH, Pang ZP, Südhof TC and Wernig M: Induced neuronal cells: How to make and define a neuron. Cell Stem Cell. 9:517–525. 2011.
6	Borgmann-Winter K, Willard SL, Sinclair D, Mirza N, Turetsky B, Berretta S and Hahn CG: Translational potential of olfactory mucosa for the study of neuropsychiatric illness. Transl Psychiatry. 5:e5272015.
7	Benítez-King G, Valdés-Tovar M, Trueta C, Galván-Arrieta T, Argueta J, Alarcón S, Lora-Castellanos A and Solís-Chagoyán H: The microtubular cytoskeleton of olfactory neurons derived from patients with schizophrenia or with bipolar disorder: Implications for biomarker characterization, neuronal physiology and pharmacological screening. Mol Cell Neurosci. 73:84–95. 2016.
8	Moberg PJ, Kamath V, Marchetto DM, Calkins ME, Doty RL, Hahn CG, Borgmann-Winter KE, Kohler CG, Gur RE and Turetsky BI: Meta-analysis of olfactory function in schizophrenia, first-degree family members, and youths at-risk for psychosis. Schizophr Bull. 40:50–59. 2014.
9	Kamath V, Turetsky BI, Calkins ME, Bilker WB, Frishberg N, Borgmann-Winter K, Kohler CG, Conroy CG, Gur RE and Moberg PJ: The effect of odor valence on olfactory performance in schizophrenia patients, unaffected relatives and at-risk youth. J Psychiatr Res. 47:1636–1641. 2013.
10	Malaspina D, Goetz R, Keller A, Messinger JW, Bruder G, Goetz D, Opler M, Harlap S, Harkavy-Friedman J and Antonius D: Olfactory processing, sex effects and heterogeneity in schizophrenia. Schizophr Res. 135:144–151. 2012.
11	Turetsky BI, Hahn C-G, Arnold SE and Moberg PJ: Olfactory receptor neuron dysfunction in schizophrenia. Neuropsychopharmacology. 34:767–774. 2009.
12	Rupp CI, Fleischhacker WW, Kemmler G, Oberbauer H, Scholtz AW, Wanko C and Hinterhuber H: Various bilateral olfactory deficits in male patients with schizophrenia. Schizophr Bull. 31:155–165. 2005.
13	Alvarado-Martínez R, Salgado-Puga K and Peña-Ortega F: Amyloid beta inhibits olfactory bulb activity and the ability to smell. PLoS One. 8:e757452013.
14	Conti MZ, Vicini-Chilovi B, Riva M, Zanetti M, Liberini P, Padovani A and Rozzini L: Odor identification deficit predicts clinical conversion from mild cognitive impairment to dementia due to Alzheimer's disease. Arch Clin Neuropsychol. 28:391–399. 2013.
15	Burón E and Bulbena A: Olfaction in affective and anxiety disorders: A review of the literature. Psychopathology. 46:63–74. 2013.
16	Arnold SE, Lee EB, Moberg PJ, Stutzbach L, Kazi H, Han LY and Trojanowski JQ: Olfactory epithelium amyloid-β and paired helical filament-tau pathology in Alzheimer disease. Ann Neurol. 67:462–469. 2010.
17	Arnold SE, Smutzer GS, Trojanowski JQ and Moberg PJ: Cellular and molecular neuropathology of the olfactory epithelium and central olfactory pathways in Alzheimer's disease and schizophrenia. Ann N Y Acad Sci. 855:762–775. 1998.
18	Arnold SE, Han L-Y, Moberg PJ, Turetsky BI, Gur RE, Trojanowski JQ and Hahn CG: Dysregulation of olfactory receptor neuron lineage in schizophrenia. Arch Gen Psychiatry. 58:829–835. 2001.
19	McCurdy RD, Féron F, Perry C, Chant DC, McLean D, Matigian N, Hayward NK, McGrath JJ and Mackay-Sim A: Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophr Res. 82:163–173. 2006.
20	Féron F, Perry C, Hirning MH, McGrath J and Mackay-Sim A: Altered adhesion, proliferation and death in neural cultures from adults with schizophrenia. Schizophr Res. 40:211–218. 2006.
21	Matigian N, Abrahamsen G, Sutharsan R, Cook AL, Vitale AM, Nouwens A, Bellette B, An J, Anderson M, Beckhouse AG, et al: Disease-specific, neurosphere-derived cells as models for brain disorders. Dis Models Mech. 3:785–798. 2010.
22	Fan Y, Abrahamsen G, McGrath JJ and Mackay-Sim A: Altered cell cycle dynamics in schizophrenia. Biol Psychiatry. 71:129–135. 2012.
23	Fan Y, Abrahamsen G, Mills R, Calderón CC, Tee JY, Leyton L, Murrell W, Cooper-White J, McGrath JJ and Mackay-Sim A: Focal adhesion dynamics are altered in schizophrenia. Biol Psychiatry. 74:418–426. 2013.
24	Hahn CG, Gomez G, Restrepo D, Friedman E, Josiassen R, Pribitkin EA, Lowry LD, Gallop RJ and Rawson NE: Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am J Psychiatry. 162:616–618. 2005.
25	Pantazopoulos H, Boyer-Boiteau A, Holbrook EH, Jang W, Hahn CG, Arnold SE and Berretta S: Proteoglycan abnormalities in olfactory epithelium tissue from subjects diagnosed with schizophrenia. Schizophr Res. 150:366–372. 2013.
26	Yang A and Tsai SJ: New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci. 18:16892017.
27	Galván-Arrieta T, Trueta C, Cercós MG, Valdés-Tovar M, Alarcón S, Oikawa J, Zamudio-Meza H and Benítez-King G: The role of melatonin in the neurodevelopmental etiology of schizophrenia: A study in human olfactory neuronal precursors. J Pineal Res. 63:2017. View Article : Google Scholar
28	Ferretjans R, de Souza RP, Panizzutti B, Ferrari P, Mantovani L, de Campos-Carli SM, Santos RR, Guimarães FC, Teixeira AL, Gama CS and Salgado JV: Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls. Braz J Psychiatry. 44:26–34. 2022.
29	Borroto-Escuela DO, Cuesta-Marti C, Lopez-Salas A, Chruścicka-Smaga B, Crespo-Ramírez M, Tesoro-Cruz E, Palacios-Lagunas DA, Perez de la Mora M, Schellekens H and Fuxe K: The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior. Front Mol Neurosci. 15:10553442022.
30	Rahman MM, Islam MR, Mim SA, Sultana N, Chellappan DK, Dua K, Kamal MA, Sharma R and Emran TB: Insights into the promising prospect of G protein and GPCR-mediated signaling in neuropathophysiology and its therapeutic regulation. Oxid Med Cell Longev. 2022:84256402022.
31	Komatsu H, Fukuchi M and Habata Y: Potential utility of biased GPCR signaling for treatment of psychiatric disorders. Int J Mol Sci. 20:201906292019.
32	Udawela M, Scarr E, Hannan AJ, Thomas EA and Dean B: Phospholipase C beta 1 expression in the dorsolateral prefrontal cortex from patients with schizophrenia at different stages of illness. Aust N Z J Psychiatry. 45:140–147. 2011.
33	Udawela M, Scarr E, Boer S, Um JY, Hannan AJ, McOmish C, Felder CC, Thomas EA and Dean B: Isoform specific differences in phospholipase C beta 1 expression in the prefrontal cortex in schizophrenia and suicide. NPJ Schizophr. 3:192017.
34	Vasco VRL, Cardinale G and Polonia P: Deletion of PLCB1 gene in schizophrenia-affected patients. J Cell Mol Med. 16:844–851. 2012.
35	Deng C, Pan B, Engel M and Huang XF: Neuregulin-1 signalling and antipsychotic treatment: Potential therapeutic targets in a schizophrenia candidate signalling pathway. Psychopharmacology (Berl). 226:201–215. 2013.
36	Féron F, Perry C, Girard SD and Mackay-Sim A: Isolation of adult stem cells from the human olfactory mucosa. Methods Mol Biol. 1059:107–114. 2013.
37	Benitez-King G, Riquelme A, Ortiz-Lopez L, Berlanga C, Rodriguez-Verdugo MS, Romo F, Calixto E, Solís-Chagoyán H, Jímenez M, Montaño LM, et al: A non-invasive method to isolate the neuronal linage from the nasal epithelium from schizophrenic and bipolar diseases. J Neurosci Methods. 201:35–45. 2011.
38	Bellon A, Wegener A, Lescallette AR, Valente M, Yang SK, Gardette R, Matricon J, Mouaffak F, Watts P, Vimeux L, et al: Transdifferentiation of human circulating monocytes into neuronal-like cells in 20 days and without reprograming. Front Mol Neurosci. 11:3232018.
39	Stoddard-Bennett T and Reijo Pera R: Treatment of Parkinson's disease through personalized medicine and induced pluripotent stem cells. Cells. 8:262019.
40	Lavoie J, Sawa A and Ishizuka K: Application of olfactory tissue and its neural progenitors to schizophrenia and psychiatric research. Curr Opin Psychiatry. 30:176–183. 2017.
41	Ellis P, Fagan BM, Magness ST, Hutton S, Taranova O, Hayashi S, McMahon A, Rao M and Pevny L: SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Dev Neurosci. 26:148–165. 2004.
42	Caprnda M, Kubatka P, Gazdikova K, Gasparova I, Valentova V, Stollarova N, La Rocca G, Kobyliak N, Dragasek J, Mozos I, et al: Immunomodulatory effects of stem cells: Therapeutic option for neurodegenerative disorders. Biomed Pharmacother. 91:60–69. 2017.
43	Zhang X, Klueber KM, Guo Z, Lu C and Roisen FJ: Adult human olfactory neural progenitors cultured in defined medium. Exp Neurol. 186:112–123. 2004.
44	Zhang X, Cai J, Klueber KM, Guo Z, Lu C, Qiu M and Roisen FJ: Induction of oligodendrocytes from adult human olfactory epithelial-derived progenitors by transcription factors. Stem Cells. 23:442–453. 2005.
45	Solís-Chagoyán H, Calixto E, Figueroa A, Montaño LM, Berlanga C, Rodríguez-Verdugo MS, Romo F, Jiménez M, Gurrola CZ, Riquelme A and Benítez-King G: Microtubule organization and L-type voltage-activated calcium current in olfactory neuronal cells obtained from patients with schizophrenia and bipolar disorder. Schizophr Res. 143:384–389. 2013.
46	Riquelme A, Valdés-Tovar M, Ugalde O, Maya-Ampudia V, Fernández M, Mendoza-Durán L, Rodríguez-Cárdenas L and Benítez-King G: Potential use of exfoliated and cultured olfactory neuronal precursors for in vivo Alzheimer's disease diagnosis: A pilot study. Cell Mol Neurobiol. 40:87–98. 2020.
47	Barrera-Conde M, Ausin K, Lachén-Montes M, Fernández-Irigoyen J, Galindo L, Cuenca-Royo A, Fernández-Avilés C, Pérez V, de la Torre R, Santamaría E and Robledo P: Cannabis use induces distinctive proteomic alterations in olfactory neuroepithelial cells of schizophrenia patients. J Pers Med. 11:1602021.
48	Delgado-Sequera A, Hidalgo-Figueroa M, Barrera-Conde M, Duran-Ruiz MC, Castro C, Fernández-Avilés C, de la Torre R, Sánchez-Gomar I, Pérez V, Geribaldi-Doldán N, et al: Olfactory neuroepithelium cells from cannabis users display alterations to the cytoskeleton and to markers of adhesion, proliferation and apoptosis. Mol Neurobiol. 58:1695–1710. 2021.
49	Muñoz-Estrada J, Benítez-King G, Berlanga C and Meza I: Altered subcellular distribution of the 75-kDa DISC1 isoform, cAMP accumulation, and decreased neuronal migration in schizophrenia and bipolar disorder: Implications for neurodevelopment. CNS Neurosci Ther. 21:446–453. 2015.
50	Kano S, Colantuoni C, Han F, Zhou Z, Yuan Q, Wilson A, Takayanagi Y, Lee Y, Rapoport J, Eaton W, et al: Genome-wide profiling of multiple histone methylations in olfactory cells: Further implications for cellular susceptibility to oxidative stress in schizophrenia. Mol Psychiatry. 18:740–742. 2013.
51	Borgmann-Winter KE, Rawson NE, Wang HY, Wang H, Macdonald ML, Ozdener MH, Yee KK, Gomez G, Xu J, Bryant B, et al: Human olfactory epithelial cells generated in vitro express diverse neuronal characteristics. Neuroscience. 158:642–653. 2009.
52	Mackay-Sim A: Concise review: Patient-derived olfactory stem cells: New models for brain diseases. Stem Cells. 30:2361–2365. 2012.
53	Rabadan MA, De La Cruz ED, Rao SB, Chen Y, Gong C, Crabtree G, Xu B, Markx S, Gogos JA, Yuste R and Tomer R: An in vitro model of neuronal ensembles. Nat Commun. 13:33402022.
54	Hoffmann A, Ziller M and Spengler D: Progress in iPSC-based modeling of psychiatric disorders. Int J Mol Sci. 20:48962019.
55	Kolagar TA, Farzaneh M, Nikkar N and Khoshnam SE: Human pluripotent stem cells in neurodegenerative diseases: Potentials, advances and limitations. Curr Stem Cell Res Ther. 15:102–110. 2020.
56	Nicholson MW, Ting CY, Chan DZH, Cheng YC, Lee YC, Hsu CC, Huang CY and Hsieh PCH: Utility of iPSC-derived cells for disease modeling, drug development, and cell therapy. Cells. 11:18532022.
57	Solis-Chagoyan H, Flores-Soto E, Valdes-Tovar M, Cercos MG, Calixto E, Montano LM, Barajas-López C, Sommer B, Aquino-Gálvez A, Trueta C and Benítez-King GA: Purinergic signaling pathway in human olfactory neuronal precursor cells. Stem Cells Int. 2019:27287862019.
58	Berridge MJ, Bootman MD and Roderick HL: Calcium signalling: Dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 4:517–529. 2003.
59	Berridge MJ: Calcium signalling and psychiatric disease: Bipolar disorder and schizophrenia. Cell and Tissue Res. 357:477–492. 2014.
60	Berridge MJ: Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion. 7:2–13. 2013.
61	Schwartz RD, Wagner JP, Yu X and Martin D: Bidirectional modulation of GABA-gated chloride channels by divalent cations: Inhibition by Ca2+ and enhancement by Mg2+. J Neurochemistry. 62:916–922. 1994.
62	Olney JW, Newcomer JW and Farber NB: NMDA receptor hypofunction model of schizophrenia. J Psychiatric Res. 33:523–533. 1999.
63	Olney JW and Farber NB: Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 52:998–1007. 1995.
64	Sharp FR, Butman M, Koistinaho J, Aardalen K, Nakki R, Massa SM, Swanson RA and Sagar SM: Phencyclidine induction of the hsp 70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels. Neuroscience. 62:1079–1092. 1994.
65	Novak G, Seeman P and Tallerico T: Schizophrenia: Elevated mRNA for calcium-calmodulin-dependent protein kinase IIbeta in frontal cortex. Brain Res Mol Brain Res. 82:95–100. 2000.
66	Benfenati F, Valtorta F, Rubenstein JL, Gorelick FS, Greengard P and Czernik AJ: Synaptic vesicle-associated Ca2+/calmodulindependent protein kinase II is a binding protein for synapsin I. Nature. 359:417–420. 1992.
67	Greengard P, Benfenati F and Valtorta F: Synapsin I, an actin-binding protein regulating synaptic vesicle traffic in the nerve terminal. Adv Second Messenger Phosphoprotein Res. 29:31–45. 1994.
68	Kantor L, Hewlett GHK and Gnegy ME: Enhanced amphetamine- and K+-mediated dopamine release in rat striatum after repeated amphetamine: Differential requirements for Ca2+- and Calmodulin-dependent phosphorylation and synaptic vesicles. J Neurosci. 19:3801–3808. 1999.
69	Popov N and Matthies H: Influence of dopamine receptor agonists and antagonists on calmodulin translocation in different brain regions. Eur J Pharmacol. 172:205–210. 1989.
70	Selemon LD and Goldman-Rakic PS: The reduced neuropil hypothesis: A circuit based model of schizophrenia. Biol Psychiatry. 45:17–25. 1999.
71	Broadbelt K, Byne W and Jones LB: Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex. Schizophr Res. 58:75–81. 2002.
72	Mattson MP: Calcium as sculptor and destroyer of neural circuitry. Exp Gerontol. 27:29–49. 1992.
73	Bird MM and Owen A: The effect of calcium ionophore A23187 on neurites from embryonic mouse spinal cord explants in culture. J Eectron Microscopy. 49:379–386. 2000.
74	Lidow MS: Calcium signaling dysfunction in schizophrenia: A unifying approach. Brain Res Brain Res Rev. 43:70–84. 2003.
75	Benes FM, McSparren J, Bird ED, SanGiovanni JP and Vincent SL: Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry. 48:996–1001. 1991.
76	Benes FM, Davidson J and Bird ED: Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch Gen Psychiatry. 43:31–35. 1986.
77	Benes FM, Kwok EW, Vincent SL and Todtenkopf MS: A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry. 44:88–97. 1998.
78	Falkai P and Bogerts B: Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci. 236:154–161. 1986.
79	Jeste DV and Lohr JB: Hippocampal pathologic findings in schizophrenia. A morphometric study. Arch Gen Psychiatry. 46:1019–1024. 1989.
80	Popken GJ, Bunney WE, Potkin SG and Jones EG: Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proc Natl Acad Sci USA. 97:9276–9280. 2000.
81	Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE Jr and Jones EG: Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients. Arch Gen Psychiatry. 53:425–436. 1996.
82	Hirai K, Yoshioka H, Kihara M, Hasegawa K, Sakamoto T, Sawada T and Fushiki S: Inhibiting neuronal migration by blocking NMDA receptors in the embryonic rat cerebral cortex: A tissue culture study. Brain Res Dev Brain Res. 114:63–67. 1999.
83	Soria JM and Valdeolmillos M: Receptor-activated calcium signals in tangentially migrating cortical cells. Cerebral Cortex. 12:831–839. 2002.
84	Velligan DI and Rao S: The epidemiology and global burden of schizophrenia. J Clin Psychiatry. 84:MS21078COM52023.
85	Boczek T, Mackiewicz J, Sobolczyk M, Wawrzyniak J, Lisek M, Ferenc B, Guo F and Zylinska L: The role of G Protein-coupled receptors (GPCRs) and calcium signaling in schizophrenia. Focus on GPCRs activated by neurotransmitters and chemokines. Cells. 10:12282021.
86	Ermakov EA, Dmitrieva EM, Parshukova DA, Kazantseva DV, Vasilieva AR and Smirnova LP: Oxidative Stress-related mechanisms in schizophrenia pathogenesis and new treatment perspectives. Oxid Med Cell Longev. 2021:88817702021.
87	Özdemir H, Eker M, Zengin B, Yılmaz DA, İşman Haznedaroğlu D, Çınar C, Kitiş Ö, Akay A and Gönül AS: Gray matter changes in patients with deficit schizophrenia and non-deficit schizophrenia. Turk Psikiyatri Derg. 23:237–246. 2012.
88	Valdés-Tovar M, Rodríguez-Ramírez AM, Rodríguez-Cárdenas L, Sotelo-Ramírez CE, Camarena B, Sanabrais-Jiménez MA, Solís-Chagoyán H, Argueta J and López-Riquelme GO: Insights into myelin dysfunction in schizophrenia and bipolar disorder. World J Psychiatry. 12:264–285. 2022.
89	Jimerson DC, Post RM, Carman JS, van Kammen DP, Wood JH, Goodwin FK and Bunney WE Jr: CSF calcium: Clinical correlates in affective illness and schizophrenia. Biol Psychiatry. 14:37–51. 1979.
90	Lewis DA and Moghaddam B: Cognitive dysfunction in schizophrenia: Convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol. 63:1372–1376. 2006.
91	Beaulieu JM, Espinoza S and Gainetdinov RR: Dopamine receptors-IUPHAR Review 13. Br J Pharmacol. 172:1–23. 2015.
92	Li YC, Kellendonk C, Simpson EH, Kandel ER and Gao WJ: D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex. Proc Natl Acad Sci USA. 108:12107–12112. 2011.
93	Takahashi H, Kato M, Takano H, Arakawa R, Okumura M, Otsuka T, Kodaka F, Hayashi M, Okubo Y, Ito H and Suhara T: Differential contributions of prefrontal and hippocampal dopamine D(1) and D(2) receptors in human cognitive functions. J Neurosci. 28:12032–12038. 2008.
94	Beaulieu JM and Gainetdinov RR: The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 63:182–217. 2011.
95	Speranza L, di Porzio U, Viggiano D, de Donato A and Volpicelli F: Dopamine: The Neuromodulator of Long-term synaptic plasticity, reward and movement control. Cells. 10:7352021.
96	Conio B, Martino M, Magioncalda P, Escelsior A, Inglese M, Amore M and Northoff G: Opposite effects of dopamine and serotonin on resting-state networks: Review and implications for psychiatric disorders. Mol Psychiatry. 25:82–93. 2020.
97	Seeman P: Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets. 10:515–531. 2006.
98	Simpson EH, Gallo EF, Balsam PD, Javitch JA and Kellendonk C: How changes in dopamine D2 receptor levels alter striatal circuit function and motivation. Mol Psychiatry. 27:436–444. 2022.
99	Schizophrenia Working Group of the Psychiatric Genomics Consortium: Biological insights from 108 schizophrenia-associated genetic loci. Nature. 511:421–427. 2014.
100	Howes O, Mccutcheon R and Stone J: Glutamate and dopamine in schizophrenia: An update for the 21st century. J Psychopharmacol. 29:97–115. 2015.
101	Goldman-Rakic P, Castner S, Svensson T, Siever L and Williams G: Targeting the dopamine D1 receptor in schizophrenia: Insights for cognitive dysfunction. Psychopharmacology (Berl). 174:3–16. 2004.
102	Jardemark K, Wadenberg ML, Grillner P and Svensson TH: Dopamine D3 and D4 receptor antagonists in the treatment of schizophrenia. Curr Opin Investig Drugs. 3:101–105. 2002.
103	Gross G, Wicke K and Drescher KU: Dopamine D₃ receptor antagonism-still a therapeutic option for the treatment of schizophrenia. Naunyn Schmiedebergs Arch Pharmacol. 386:155–166. 2013.
104	Maramai S, Gemma S, Brogi S, Campiani G, Butini S, Stark H and Brindisi M: Dopamine D3 receptor antagonists as potential therapeutics for the treatment of neurological diseases. Front Neurosci. 10:4512016.
105	Motiejunaite J, Amar L and Vidal-Petiot E: Adrenergic receptors and cardiovascular effects of catecholamines. Ann Endocrinol (Paris). 82:193–197. 2021.
106	Perez DM and Doze VA: Cardiac and neuroprotection regulated by α(1)-adrenergic receptor subtypes. J Recept Signal Transduct Res. 31:98–110. 2011.
107	Jensen BC, Swigart PM, De Marco T, Hoopes C and Simpson PC: {alpha}1-Adrenergic receptor subtypes in nonfailing and failing human myocardium. Circ Heart Fail. 2:654–663. 2009.
108	Yamamoto K and Hornykiewicz O: Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 28:913–922. 2004.
109	Arnsten AT: Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology (Berl). 174:25–31. 2004.
110	Atzori M, Cuevas-Olguin R, Esquivel-Rendon E, Garcia-Oscos F, Salgado-Delgado RC, Saderi N, Miranda-Morales M, Treviño M, Pineda JC and Salgado H: Locus ceruleus norepinephrine release: A central regulator of CNS Spatio-temporal activation? Front Synaptic Neurosci. 8:252016.
111	Birnbaum SG, Yuan PX, Wang M, Vijayraghavan S, Bloom AK, Davis DJ, Gobeske KT, Sweatt JD, Manji HK and Arnsten AF: Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science. 306:882–884. 2004.
112	Phillips WA, Larkum ME, Harley CW and Silverstein SM: The effects of arousal on apical amplification and conscious state. Neurosci Conscious. 2016:niw0152016.
113	Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, et al: DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 310:1187–1191. 2005.
114	Millar JK, Mackie S, Clapcote SJ, Murdoch H, Pickard BS, Christie S, Muir WJ, Blackwood DH, Roder JC, Houslay MD and Porteous DJ: Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness. J Physiol. 584:401–405. 2007.
115	Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, et al: α2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 129:397–410. 2007.
116	Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, Mazer JA, Lee D and Arnsten AF: Neuronal basis of age-related working memory decline. Nature. 476:210–213. 2011.
117	Valero-Aracama MJ, Reboreda A, Arboit A, Sauvage M and Yoshida M: Noradrenergic suppression of persistent firing in hippocampal CA1 pyramidal cells through cAMP-PKA pathway. eNeuro. 8:ENEURO.0440–20.2020. 2021.
118	Ramos BP, Colgan L, Nou E, Ovadia S, Wilson SR and Arnsten AF: The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys. Biol Psychiatry. 58:894–900. 2005.
119	Ramos BP, Colgan LA, Nou E and Arnsten AFT: β2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals. Neurobiol Aging. 29:1060–1069. 2008.
120	Clark DA, Arranz MJ, Mata I, Lopéz-Ilundain J, Pérez-Nievas F and Kerwin RW: Polymorphisms in the promoter region of the alpha1A-adrenoceptor gene are associated with schizophrenia/schizoaffective disorder in a Spanish isolate population. Biol Psychiatry. 58:435–439. 2005.
121	Lochman J, Plesník J, Janout V, Povová J, Míšek I, Dvořáková D and Šerý O: Interactive effect of MTHFR and ADRA2A gene polymorphisms on pathogenesis of schizophrenia. Neuro Endocrinol Lett. 34:792–797. 2013.
122	Vares M, Saetre P, Deng H, Cai G, Liu X, Hansen T, Rasmussen HB, Werge T, Melle I, Djurovic S, et al: Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 153B:610–618. 2010.
123	Lu ML, Ku WC, Syifa N, Hu SC, Chou CT, Wu YH, Kuo PH, Chen CH, Chen WJ and Wu TH: Developing a sensitive platform to measure 5-methyltetrahydrofolate in subjects with MTHFR and PON1 gene polymorphisms. Nutrients. 14:33202022.
124	Dean B and Scarr E: Muscarinic M1 and M4 receptors: Hypothesis driven drug development for schizophrenia. Psychiatry Res. 288:1129892020.
125	Dean B, Bakker G, Ueda HR, Tobin AB, Brown A and Kanaan RAA: A growing understanding of the role of muscarinic receptors in the molecular pathology and treatment of schizophrenia. Front Cell Neurosci. 17:11243332023.
126	Teal LB, Gould RW, Felts AS and Jones CK: Selective allosteric modulation of muscarinic acetylcholine receptors for the treatment of schizophrenia and substance use disorders. Adv Pharmacol. 86:153–196. 2019.
127	Crook JM, Tomaskovic-Crook E, Copolov DL and Dean B: Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: A study of Brodmann's Areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am J Psychiatry. 158:918–925. 2001.
128	Zavitsanou K, Katsifis A, Mattner F and Huang XF: Investigation of M1/M4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder. Neuropsychopharmacology. 29:619–625. 2004.
129	Crook JM, Tomaskovic-Crook E, Copolov DL and Dean B: Decreased muscarinic receptor binding in subjects with schizophrenia: A study of the human hippocampal formation. Biol Psychiatry. 48:381–388. 2000.
130	Dean B, Crook JM, Opeskin K, Hill C, Keks N and Copolov DL: The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. Mol Psychiatry. 1:54–58. 1996.
131	Liao DL, Hong CJ, Chen HM, Chen YE, Lee SM, Chang CY, Chen H and Tsai SJ: Association of muscarinic m1 receptor genetic polymorphisms with psychiatric symptoms and cognitive function in schizophrenic patients. Neuropsychobiology. 48:72–76. 2003.
132	Scarr E, Craig JM, Cairns MJ, Seo MS, Galati JC, Beveridge NJ, Gibbons A, Juzva S, Weinrich B, Parkinson-Bates M, et al: Decreased cortical muscarinic M1 receptors in schizophrenia are associated with changes in gene promoter methylation, mRNA and gene targeting microRNA. Transl Psychiatry. 3:e2302013.
133	Scarr E, Um JY, Cowie TF and Dean B: Cholinergic muscarinic M4 receptor gene polymorphisms: A potential risk factor and pharmacogenomic marker for schizophrenia. Schizophr Res. 146:279–284. 2013.
134	De Luca V, Wang H, Squassina A, Wong GW, Yeomans J and Kennedy JL: Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia. Neuropsychobiology. 50:124–127. 2004.
135	Anagnostaras SG, Murphy GG, Hamilton SE, Mitchell SL, Rahnama NP, Nathanson NM and Silva AJ: Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci. 6:51–58. 2003.
136	Thomsen M, Wess J, Fulton BS, Fink-Jensen A and Caine SB: Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice. Psychopharmacology. 208:401–416. 2010.
137	Felder CC, Porter AC, Skillman TL, Zhang L, Bymaster FP, Nathanson NM, Hamilton SE, Gomeza J, Wess J and McKinzie DL: Elucidating the role of muscarinic receptors in psychosis. Life Sci. 68:2605–2613. 2001.
138	Koshimizu H, Leiter LM and Miyakawa T: M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition. Mol Brain. 5:102012.
139	Dencker D, Wörtwein G, Weikop P, Jeon J, Thomsen M, Sager TN, Mørk A, Woldbye DP, Wess J and Fink-Jensen A: Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline. J Neurosci. 31:5905–5908. 2011.
140	Woolley ML, Carter HJ, Gartlon JE, Watson JM and Dawson LA: Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice. Eur J Pharmacol. 603:147–149. 2009.
141	Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, Wess J, McKinzie DL, Felder C and Nomikos GG: M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: Relevance to the pathophysiology and treatment of related CNS pathologies. FASEB J. 18:1410–1412. 2004.
142	Zhang W, Yamada M, Gomeza J, Basile AS and Wess J: Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice. J Neurosci. 22:6347–6352. 2002.
143	Thomsen M, Wörtwein G, Fink-Jensen A, Woldbye DP, Wess J and Caine SB: Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice. Psychopharmacology. 192:97–110. 2007.
144	Wang H, Ng K, Hayes D, Gao X, Forster G, Blaha C and Yeomans J: Decreased Amphetamine-induced locomotion and improved latent inhibition in mice mutant for the M5 muscarinic receptor gene found in the human 15q schizophrenia region. Neuropsychopharmacology. 29:2126–2139. 2004.
145	Abad NH, Doulatabad NS, Mohammadi A and Srazi HR: Treatment of visual hallucinations in schizophrenia by acetylcholinesterase inhibitors: A case report. Iran J Osychiatry. 6:161–163. 2011.
146	Patel SS, Attard A, Jacobsen P and Shergill S: Acetylcholinesterase Inhibitors (AChEI's) for the treatment of visual hallucinations in schizophrenia: A case report. BMC Psychiatry. 10:682010.
147	Mancama D, Mata I, Kerwin RW and Arranz MJ: Choline acetyltransferase variants and their influence in schizophrenia and olanzapine response. Am J Med Genet B Neuropsychiatr Genet. 144B:849–853. 2007.
148	Niswender CM and Conn PJ: Metabotropic glutamate receptors: Physiology, pharmacology, and disease. Ann Rev Pharmacol Toxicol. 50:295–322. 2010.
149	Kim JH, Marton J, Ametamey SM and Cumming P: A review of molecular imaging of glutamate receptors. Molecules. 25:47492020.
150	Crupi R, Impellizzeri D and Cuzzocrea S: Role of metabotropic glutamate receptors in neurological disorders. Front Mol Neurosci. 12:202019.
151	Ayoub MA, Angelicheva D, Vile D, Chandler D, Morar B, Cavanaugh JA, Visscher PM, Jablensky A, Pfleger KD and Kalaydjieva L: Deleterious GRM1 mutations in schizophrenia. PLoS One. 7:e328492012.
152	Volk DW, Eggan SM and Lewis DA: Alterations in metabotropic glutamate receptor 1α and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. Am J Psychiatry. 167:1489–1498. 2010.
153	Aiba A, Chen C, Herrup K, Rosenmund C, Stevens CF and Tonegawa S: Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell. 79:365–375. 1994.
154	Gil-Sanz C, Delgado-García JM, Fairén A and Gruart A: Involvement of the mGluR1 receptor in hippocampal synaptic plasticity and associative learning in behaving mice. Cerebral Cortex. 18:1653–1663. 2008.
155	Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, Zwingman TA and Tonegawa S: Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell. 79:377–388. 1994.
156	Brody SA, Conquet F and Geyer MA: Disruption of prepulse inhibition in mice lacking mGluR1. Eur J Neurosci. 18:3361–3366. 2003.
157	Maksymetz J, Moran SP and Conn PJ: Targeting metabotropic glutamate receptors for novel treatments of schizophrenia. Mol Brain. 10:152017.
158	Matosin N and Newell KA: Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia. Neurosci Biobehav Rev. 37:256–268. 2013.
159	Brody SA, Dulawa SC, Conquet F and Geyer MA: Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors. Mol Psychiatry. 9:35–41. 2004.
160	Liang W, Hou Y, Huang W, Wang Y, Jiang T, Huang X, Wang Z, Wu F, Zheng J, Zhang J, et al: Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission. Sci Adv. 8:eabn73572022.
161	Campbell UC, Lalwani K, Hernandez L, Kinney GG, Conn PJ and Bristow LJ: The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats. Psychopharmacology. 175:310–318. 2004.
162	Henry SA, Lehmann-Masten V, Gasparini F, Geyer MA and Markou A: The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology. 43:1199–1209. 2002.
163	Homayoun H, Stefani MR, Adams BW, Tamagan GD and Moghaddam B: Functional interaction between NMDA and mGlu5 receptors: Effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology. 29:1259–1269. 2004.
164	Zou D, Huang J, Wu X and Li L: Metabotropic glutamate subtype 5 receptors modulate fear-conditioning induced enhancement of prepulse inhibition in rats. Neuropharmacology. 52:476–486. 2007.
165	Semenova S and Markou A: The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task. Neuropharmacology. 52:863–872. 2007.
166	Trepanier C, Lei G, Xie YF and Macdonald JF: Group II metabotropic glutamate receptors modify N-methyl-D-aspartate receptors via Src kinase. Sci Rep. 3:9262013.
167	Tyszkiewicz JP, Gu Z, Wang X, Cai X and Yan Z: Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C-dependent mechanism in pyramidal neurones of rat prefrontal cortex. J Physiol. 554:765–777. 2004.
168	Cheng J, Liu W, Duffney LJ and Yan Z: SNARE proteins are essential in the potentiation of NMDA receptors by group II metabotropic glutamate receptors. J Physiol. 591:3935–3947. 2013.
169	Uslaner JM, Smith SM, Huszar SL, Pachmerhiwala R, Hinchliffe RM, Vardigan JD and Hutson PH: Combined administration of an mGlu2/3 receptor agonist and a 5-HT 2A receptor antagonist markedly attenuate the psychomotoractivating and neurochemical effects of psychostimulants. Psychopharmacology. 206:641–651. 2009.
170	Campusano JM, Abarca J, Forray MI, Gysling K and Bustos G: Modulation of dendritic release of dopamine by metabotropic glutamate receptors in rat substantia nigra. Biochem Pharmacol. 63:1343–1352. 2002.
171	Chaki S, Yoshikawa R and Okuyama S: Group II metabotropic glutamate receptor-mediated regulation of dopamine release from slices of rat nucleus accumbens. Neurosci Lett. 404:182–186. 2006.
172	Hu G, Duffy P, Swanson C, Ghasemzadeh MB and Kalivas PW: The regulation of dopamine transmission by metabotropic glutamate receptors. J Pharmacol Exp Ther. 289:412–416. 1999.
173	Johnson KA, Mateo Y and Lovinger DM: Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum. Neuropharmacology. 117:114–123. 2017.
174	Schoepp DD, Jane DE and Monn JA: Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology. 38:1431–1476. 1999.
175	Moghaddam B and Adams BW: Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 281:1349–1352. 1998.
176	Cartmell J, Monn JA and Schoepp DD: The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther. 291:161–170. 1999.
177	Galici R, Echemendia NG, Rodriguez AL and Conn PJ: A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J Pharmacol Exp Ther. 315:1181–1187. 2005.
178	Kawaura K, Karasawa J and Hikichi H: Stimulation of the metabotropic glutamate (mGlu) 2 receptor attenuates the MK-801-induced increase in the immobility time in the forced swimming test in rats. Pharmacol Rep. 68:80–84. 2016.
179	Homayoun H, Jackson ME and Moghaddam B: Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. J Neurophysiol. 93:1989–2001. 2005.
180	Kłodzinska A, Bijak M, Tokarski K and Pilc A: Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice. Pharmacol Biochem Behav. 73:327–332. 2002.
181	Matrisciano F, Tueting P, Maccari S, Nicoletti F and Guidotti A: Pharmacological activation of group-II metabotropic glutamate receptors corrects a schizophrenia-like phenotype induced by prenatal stress in mice. Neuropsychopharmacology. 37:929–938. 2012.
182	Jones CA, Brown AM, Auer DP and Fone KCF: The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat. Psychopharmacology. 214:269–283. 2011.
183	Harich S, Gross G and Bespalov A: Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment. Psychopharmacology. 192:511–519. 2007.
184	Hikichi H, Kaku A, Karasawa JI and Chaki S: Stimulation of metabotropic glutamate (mGlu) 2 receptor and blockade of mGlu1 receptor improve social memory impairment elicited by MK-801 in rats. J Pharmacol Sci. 122:10–16. 2013.
185	Wierońska JM, Acher FC, Sławińska A, Gruca P, Łasoń-Tyburkiewicz M, Papp M and Pilc A: The antipsychotic-like effects of the mGlu group III orthosteric agonist, LSP1-2111, involves 5-HT1A signalling. Psychopharmacology. 227:711–725. 2013.
186	Greco B, Invernizzi RW and Carli M: Phencyclidine-induced impairment in attention and response control depends on the background genotype of mice: Reversal by the mGLU2/3 receptor agonist LY379268. Psychopharmacology. 179:68–76. 2005.
187	Higgins GA, Ballard TM, Kew JN, Richards JG, Kemp JA, Adam G, Woltering T, Nakanishi S and Mutel V: Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology. 46:907–917. 2004.
188	Amitai N and Markou A: Effects of metabotropic glutamate receptor 2/3 agonism and antagonism on schizophrenia-like cognitive deficits induced by phencyclidine in rats. Eur J Pharmacol. 639:67–80. 2010.
189	González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, et al: Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 452:93–97. 2008.
190	Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, et al: Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell. 147:1011–1023. 2011.
191	Moreno JL, Miranda-Azpiazu P, García-Bea A, Younkin J, Cui M, Kozlenkov A, Ben-Ezra A, Voloudakis G, Fakira AK, Baki L, et al: Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal. 9:ra52016.
192	Kurita M, Holloway T, García-Bea A, Kozlenkov A, Friedman AK, Moreno JL, Heshmati M, Golden SA, Kennedy PJ, Takahashi N, et al: HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci. 15:1245–1254. 2012.
193	Pałucha-Poniewiera A, Kłodzińska A, Stachowicz K, Tokarski K, Hess G, Schann S, Frauli M, Neuville P and Pilc A: Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents. Neuropharmacology. 55:517–524. 2008.
194	Pekhletski R, Gerlai R, Overstreet LS, Huang X-P, Agopyan N, Slater NT, Abramow-Newerly W, Roder JC and Hampson DR: Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. J Neurosci. 16:6364–6373. 1996.
195	Gerlai R, Roder JC and Hampson DR: Altered spatial learning and memory in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. Behav Neurosci. 112:525–532. 1998.
196	Snead OC, Banerjee PK, Burnham M and Hampson D: Modulation of absence seizures by the GABA(A) receptor: A critical role for metabotropic glutamate receptor 4 (mGluR4). J Neurosci. 20:6218–6224. 2000.
197	Wierońska JM, Stachowicz K, Acher F, Lech T and Pilc A: Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia. Psychopharmacology. 220:481–494. 2012.
198	Woźniak M, Acher F, Marciniak M, Lasoń-Tyburkiewicz M, Gruca P, Papp M, Pilc A and Wierońska JM: Involvement of GABAB receptor signaling in Antipsychotic-like action of the novel orthosteric agonist of the mGlu4 receptor, LSP4-2022. Curr Neuropharmacol. 14:413–426. 2016.
199	Masu M, Iwakabe H, Tagawa Y, Miyoshi T, Yamashita M, Fukuda Y, Sasaki H, Hiroi K, Nakamura Y, Shigemoto R, et al: Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell. 80:757–765. 1995.
200	Sugihara H, Inoue T, Nakanishi S and Fukuda Y: A late ON response remains in visual response of the mGluR6-deficient mouse. Neuroscience Lett. 233:137–140. 1997.
201	Hosak L, Sery O, Sadykov E and Studnicka J: Retinal abnormatilites as a diagnostic or prognostic marker of schizophrenia. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 162:159–164. 2018.
202	Bernardin F, Schwitzer T, Angioi-Duprez K, Giersch A, Jansen C, Schwan R and Laprevote V: Retinal ganglion cells dysfunctions in schizophrenia patients with or without visual hallucinations. Schizophr Res. 219:47–55. 2020.
203	Sansig G, Bushell TJ, Clarke VRJ, Rozov A, Burnashev N, Portet C, Gasparini F, Schmutz M, Klebs K, Shigemoto R, et al: Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. J Neurosci. 21:8734–8745. 2001.
204	O'Connor RM, Finger BC, Flor PJ and Cryan JF: Metabotropic glutamate receptor 7: At the interface of cognition and emotion. Eur J Pharmacol. 639:123–131. 2010.
205	Bushell TJ, Sansig G, Collett VJ, Van Der Putten H and Collingridge GL: Altered Short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7. ScientificWorldJournal. 2:730–737. 2002.
206	Hölscher C, Schmid S, Pilz PK, Sansig G, van der Putten H and Plappert CF: Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory. Behav Brain Res. 154:473–481. 2004.
207	Hölscher C, Schmid S, Pilz PKD, Sansig G, Van Der Putten H and Plappert CF: Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory. Learning Memory. 12:450–455. 2005.
208	Goddyn H, Callaerts-Vegh Z, Stroobants S, Dirikx T, Vansteenwegen D, Hermans D, van der Putten H and D'Hooge R: Deficits in acquisition and extinction of conditioned responses in mGluR7 knockout mice. Neurobiol Learn Mem. 90:103–111. 2008.
209	Callaerts-Vegh Z, Beckers T, Ball SM, Baeyens F, Callaerts PF, Cryan FJ, Molnar E and D'Hooge R: Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice. J Neurosci. 26:6573–6582. 2006.
210	Masugi M, Yokoi M, Shigemoto R, Muguruma K, Watanabe Y, Sansig G, van der Putten H and Nakanishi S: Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion. J Neurosci. 19:955–963. 1999.
211	Kalinichev M, Rouillier M, Girard F, Royer-Urios I, Bournique B, Finn T, Charvin D, Campo B, Le Poul E, Mutel V, et al: ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: In vitro and In vivo characterization. J Pharmacol Exp Ther. 344:624–636. 2013.
212	Suzuki G, Tsukamoto N, Fushiki H, Kawagishi A, Nakamura M, Kurihara H, Mitsuya M, Ohkubo M and Ohta H: In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists. J Pharmacol Exp Ther. 323:147–156. 2007.
213	Cieślik P, Woźniak M, Kaczorowska K, Brański P, Burnat G, Chocyk A, Bobula B, Gruca P, Litwa E, Pałucha-Poniewiera A, et al: Negative allosteric modulators of mGlu7 receptor as putative antipsychotic drugs. Front Mol Neurosci. 11:3162018.
214	Zhai J, Tian MT, Wang Y, Yu JL, Köster A, Baez M and Nisenbaum ES: Modulation of lateral perforant path excitatory responses by metabotropic glutamate 8 (mGlu8) receptors. Neuropharmacology. 43:223–230. 2002.
215	Gerlai R, Adams B, Fitch T, Chaney S and Baez M: Performance deficits of mGluR8 knockout mice in learning tasks: The effects of null mutation and the background genotype. Neuropharmacology. 43:235–249. 2002.
216	Robbins MJ, Starr KR, Honey A, Soffin EM, Rourke C, Jones GA, Kelly FM, Strum J, Melarange RA, Harris AJ, et al: Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Brain Res. 1152:215–227. 2007.
217	Gicquel T, Le Daré B, Boichot E and Lagente V: Purinergic receptors: New targets for the treatment of gout and fibrosis. Fundam Clin Pharmacol. 31:136–146. 2017.
218	Magni G and Ceruti S: P2Y purinergic receptors: New targets for analgesic and antimigraine drugs. Biochem Pharmacol. 85:466–477. 2013.
219	Weissman TA, Riquelme PA, Ivic L, Flint AC and Kriegstein AR: Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex. Neuron. 43:647–661. 2004.
220	Ribeiro DE, Glaser T, Oliveira-Giacomelli Á and Ulrich H: Purinergic receptors in neurogenic processes. Brain Res Bull. 151:3–11. 2019.
221	Koch H, Bespalov A, Drescher K, Franke H and Krügel U: Impaired cognition after stimulation of P2Y1 receptors in the rat medial prefrontal cortex. Neuropsychopharmacology. 40:305–314. 2015.
222	Huang L, Otrokocsi L and Sperlágh B: Role of P2 receptors in normal brain development and in neurodevelopmental psychiatric disorders. Brain Res Bull. 151:55–64. 2019.
223	Leung LS and Ma J: Medial septum modulates hippocampal gamma activity and prepulse inhibition in an N-methyl-d-aspartate receptor antagonist model of schizophrenia. Schizophr Res. 198:36–44. 2018.
224	Schroeder A, Hudson M, Du X, Wu YWC, Nakamura J, van den Buuse M, Jones NC and Hill RA: Estradiol and raloxifene modulate hippocampal gamma oscillations during a spatial memory task. Psychoneuroendocrinology. 78:85–92. 2017.
225	Lindberg D, Shan D, Ayers-Ringler J, Oliveros A, Benitez J, Prieto M, McCullumsmith R and Choi DS: Purinergic signaling and energy homeostasis in psychiatric disorders. Curr Mol Med. 15:275–295. 2015.
226	Cheffer A, Castillo ARG, Corrêa-Velloso J, Gonçalves MCB, Naaldijk Y, Nascimento IC, Burnstock G and Ulrich H: Purinergic system in psychiatric diseases. Mol Psychiatry. 23:94–106. 2018.
227	Lara DR, Dall'Igna OP, Ghisolfi ES and Brunstein MG: Involvement of adenosine in the neurobiology of schizophrenia and its therapeutic implications. Prog Neuropsychopharmacol Biol Psychiatry. 30:617–629. 2006.
228	Matos M, Shen HY, Augusto E, Wang Y, Wei CJ, Wang YT, Agostinho P, Boison D, Cunha RA and Chen JF: Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: Relevance to schizophrenia. Biol Psychiatry. 78:763–774. 2015.
229	Marques TR, Natesan S, Rabiner EA, Searle GE, Gunn R, Howes OD and Kapur S: Adenosine A2A receptor in schizophrenia: An In vivo brain PET imaging study. Psychopharmacology. 239:3439–3445. 2022.
230	Wexler EM, Paucer A, Kornblum HI, Palmer TD and Geschwind DH: Endogenous Wnt signaling maintains neural progenitor cell potency. Stem Cells. 27:1130–1141. 2009.
231	Niehrs C and Acebron SP: Mitotic and mitogenic Wnt signalling. EMBO J. 31:2705–2713. 2012.
232	Huang YL and Niehrs C: Polarized wnt signaling regulates ectodermal cell fate in xenopus. Dev Cell. 29:250–257. 2014.
233	Loh Kyle M, van Amerongen R and Nusse R: Generating cellular diversity and spatial form: Wnt signaling and the evolution of multicellular animals. Dev Cell. 38:643–655. 2016.
234	Vallée A: Neuroinflammation in schizophrenia: The key role of the WNT/β-catenin pathway. Int J Mol Sci. 23:28102022.
235	Anand AA, Khan M, V M and Kar D: The molecular basis of Wnt/β-catenin signaling pathways in neurodegenerative diseases. Int J Cell Biol. 2023:92960922023.
236	Al-Harthi L: Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. J Neuroimmune Pharmacol. 7:725–730. 2012.
237	Schmitt A, Simons M, Cantuti-Castelvetri L and Falkai P: A new role for oligodendrocytes and myelination in schizophrenia and affective disorders? Eur Arch Psychiatry Clin Neurosci. 269:371–372. 2019.
238	Cotter D, Kerwin R, al-Sarraji S, Brion JP, Chadwich A, Lovestone S, Anderton B and Everall I: Abnormalities of Wnt signalling in schizophrenia-evidence for neurodevelopmental abnormality. Neuroreport. 9:1379–1383. 1998.
239	Liu X, Low SK, Atkins JR, Wu JQ, Reay WR, Cairns HM, Green MJ, Schall U, Jablensky A, Mowry B, et al: Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort. Aust N Z J Psychiatry. 54:902–908. 2020.
240	Katsu T, Ujike H, Nakano T, Tanaka Y, Nomura A, Nakata K, Takaki M, Sakai A, Uchida N, Imamura T and Kuroda S: The human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia. Neurosci Lett. 353:53–56. 2003.
241	Zhang Y, Yu X, Yuan Y, Ling Y, Ruan Y, Si T, Lu T, Wu S, Gong X, Zhu Z, et al: Positive association of the human frizzled 3 (FZD3) gene haplotype with schizophrenia in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet. 129B:16–19. 2004.
242	Yang J, Si T, Ling Y, Ruan Y, Han Y, Wang X, Zhang H, Kong Q, Li X, Liu C, et al: Association study of the human FZD3 locus with schizophrenia. Biol Psychiatry. 54:1298–1301. 2003.
243	Kishimoto M, Ujike H, Okahisa Y, Kotaka T, Takaki M, Kodama M, Inada T, Yamada M, Uchimura N, Iwata N, et al: The Frizzled 3 gene is associated with methamphetamine psychosis in the Japanese population. Behav Brain Funct. 4:372008.
244	Hoseth EZ, Krull F, Dieset I, Mørch RH, Hope S, Gardsjord ES, Steen NE, Melle I, Brattbakk HR, Steen VM, et al: Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder. Transl Psychiatry. 8:552018.
245	Castillo PE, Younts TJ, Chávez AE and Hashimotodani Y: Endocannabinoid signaling and synaptic function. Neuron. 76:70–81. 2012.
246	Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, et al: International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB₁ and CB₂. Pharmacol Rev. 62:588–631. 2010.
247	Downer EJ: Cannabinoids and innate immunity: Taking a toll on neuroinflammation. ScientificWorldJournal. 11:855–865. 2011.
248	Galindo L, Moreno E, López-Armenta F, Guinart D, Cuenca-Royo A, Izquierdo-Serra M, Xicota L, Fernandez C, Menoyo E, Fernández-Fernández JM, et al: Cannabis users show enhanced expression of CB₁-5HT_2A receptor heteromers in olfactory neuroepithelium cells. Mol Neurobiol. 55:6347–6361. 2018.
249	Compagnucci C, Di Siena S, Bustamante MB, Di Giacomo D, Di Tommaso M, Maccarrone M, Grimaldi P and Sette C: Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PLoS One. 8:e542712013.
250	Goncalves MB, Suetterlin P, Yip P, Molina-Holgado F, Walker DJ, Oudin MJ, Zentar MP, Pollard S, Yáñez-Muñoz RJ, Williams G, et al: A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner. Mol Cell Neurosci. 38:526–536. 2008.
251	Molina-Holgado F, Rubio-Araiz A, García-Ovejero D, Williams RJ, Moore JD, Arévalo-Martín A, Gómez-Torres O and Molina-Holgado E: CB2 cannabinoid receptors promote mouse neural stem cell proliferation. Eur J Neurosci. 25:629–634. 2007.
252	Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzmán M and Galve-Roperh I: Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J. 20:2405–2407. 2006.
253	Palazuelos J, Ortega Z, Díaz-Alonso J, Guzmán M and Galve-Roperh I: CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J Biol Chem. 287:1198–1209. 2012.
254	Müller-Vahl KR and Emrich HM: Cannabis and schizophrenia: Towards a cannabinoid hypothesis of schizophrenia. Expert Rev Neurother. 8:1037–1048. 2008.
255	Navarro D, Gasparyan A, Navarrete F, Torregrosa AB, Rubio G, Marín-Mayor M, Acosta GB, Garcia-Gutiérrez MS and Manzanares J: Molecular alterations of the endocannabinoid system in psychiatric disorders. Int J Mol Sci. 23:47642022.
256	Tao R, Li C, Jaffe AE, Shin JH, Deep-Soboslay A, Yamin R, Weinberger DR, Hyde TM and Kleinman JE: Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia. Transl Psychiatry. 10:1582020.
257	Volk DW, Eggan SM, Horti AG, Wong DF and Lewis DA: Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia. Schizophr Res. 159:124–129. 2014.
258	Wong DF, Kuwabara H, Horti AG, Raymont V, Brasic J, Guevara M, Ye W, Dannals RF, Ravert HT, Nandi A, et al: Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage. 52:1505–1513. 2010.
259	García-Gutiérrez MS, García-Bueno B, Zoppi S, Leza JC and Manzanares J: Chronic blockade of cannabinoid CB2 receptors induces anxiolytic-like actions associated with alterations in GABA(A) receptors. Br J Pharmacol. 165:951–964. 2012.
260	Hu B, Doods H, Treede RD and Ceci A: Depression-like behaviour in rats with mononeuropathy is reduced by the CB2-selective agonist GW405833. Pain. 143:206–212. 2009.
261	Suárez J, Llorente R, Romero-Zerbo SY, Mateos B, Bermúdez-Silva FJ, de Fonseca FR and Viveros MP: Early maternal deprivation induces gender-dependent changes on the expression of hippocampal CB(1) and CB(2) cannabinoid receptors of neonatal rats. Hippocampus. 19:623–632. 2009.
262	Hamdani N, Tabeze JP, Ramoz N, Ades J, Hamon M, Sarfati Y, Boni C and Gorwood P: The CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia. Eur Neuropsychopharmacol. 18:34–40. 2008.
263	Pan Y, Gao F, Zhao S, Han J and Chen F: Role of the SphK-S1P-S1PRs pathway in invasion of the nervous system by SARS-CoV-2 infection. Clin Exp Pharmacol Physiol. 48:637–650. 2021.
264	Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C and Bruni P: Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: Role of S1P receptors. Biochim Biophys Acta. 1823:439–450. 2012.
265	Shen H, Zhou E, Wei X, Fu Z, Niu C, Li Y, Pan B, Mathew AV, Wang X, Pennathur S, et al: High density lipoprotein promotes proliferation of adipose-derived stem cells via S1P1 receptor and Akt, ERK1/2 signal pathways. Stem Cell Res Ther. 6:952015.
266	Kimura T, Boehmler AM, Seitz G, Kuçi S, Wiesner T, Brinkmann V, Kanz L and Möhle R: The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells. Blood. 103:4478–4486. 2004.
267	Anderson G and Maes M: Reconceptualizing adult neurogenesis: Role for sphingosine-1-phosphate and fibroblast growth factor-1 in co-ordinating astrocyte-neuronal precursor interactions. CNS Neurol Disord Drug Targets. 13:126–136. 2014.
268	Esaki K, Balan S, Iwayama Y, Shimamoto-Mitsuyama C, Hirabayashi Y, Dean B and Yoshikawa T: Evidence for altered metabolism of sphingosine-1-phosphate in the corpus callosum of patients with schizophrenia. Schizophr Bull. 46:1172–1181. 2020.
269	Chand GB, Jiang H, Miller JP, Rhodes CH, Tu Z and Wong DF: Differential Sphingosine-1-phosphate Receptor-1 protein expression in the dorsolateral prefrontal cortex between schizophrenia type 1 and type 2. Front Psychiatry. 13:8279812022.
270	Brothers SP and Wahlestedt C: Therapeutic potential of neuropeptide Y (NPY) receptor ligands. EMBO Mol Med. 2:429–439. 2010.
271	Lindner D, Stichel J and Beck-Sickinger AG: Molecular recognition of the NPY hormone family by their receptors. Nutrition. 24:907–917. 2008.
272	Howell OW, Doyle K, Goodman JH, Scharfman HE, Herzog H, Pringle A, Beck-Sickinger AG and Gray WP: Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus. J Neurochem. 93:560–570. 2005.
273	Hansel DE, Eipper BA and Ronnett GV: Neuropeptide Y functions as a neuroproliferative factor. Nature. 410:940–944. 2001.
274	Montani G, Tonelli S, Elsaesser R, Paysan J and Tirindelli R: Neuropeptide Y in the olfactory microvillar cells. Eur J Neurosci. 24:20–24. 2006.
275	Santos-Carvalho A, Elvas F, Alvaro AR, Ambrósio AF and Cavadas C: Neuropeptide Y receptors activation protects rat retinal neural cells against necrotic and apoptotic cell death induced by glutamate. Cell Death Dis. 4:e6362013.
276	Thiriet N, Agasse F, Nicoleau C, Guégan C, Vallette F, Cadet JL, Jaber M, Malva JO and Coronas V: NPY promotes chemokinesis and neurogenesis in the rat subventricular zone. J Neurochem. 116:1018–1027. 2011.
277	Spencer B, Potkar R, Metcalf J, Thrin I, Adame A, Rockenstein E and Masliah E: Systemic central nervous system (CNS)-targeted delivery of neuropeptide Y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of alzheimer disease. J Biol Chem. 291:1905–1920. 2016.
278	Decressac M, Prestoz L, Veran J, Cantereau A, Jaber M and Gaillard A: Neuropeptide Y stimulates proliferation, migration and differentiation of neural precursors from the subventricular zone in adult mice. Neurobiol Dis. 34:441–449. 2009.
279	Mellios N, Huang HS, Baker SP, Galdzicka M, Ginns E and Akbarian S: Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry. 65:1006–1014. 2009.
280	Morris HM, Stopczynski RE and Lewis DA: NPY mRNA expression in the prefrontal cortex: Selective reduction in the superficial white matter of subjects with schizoaffective disorder. Schizophr Res. 115:261–269. 2009.
281	Stadlbauer U, Langhans W and Meyer U: Administration of the Y2 receptor agonist PYY3-36 in mice induces multiple behavioral changes relevant to schizophrenia. Neuropsychopharmacology. 38:2446–2455. 2013.
282	Stahl SM: Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: Dopamine, serotonin, and glutamate. CNS Spectrums. 23:187–191. 2018.
283	Miller MC and Mayo KH: Chemokines from a structural perspective. Int J Mol Sci. 18:20882017.
284	Ermakov EA, Mednova IA, Boiko AS, Buneva VN and Ivanova SA: Chemokine dysregulation and neuroinflammation in schizophrenia: A systematic review. Int J Mol Sci. 24:22152023.
285	Sugiyama T, Kohara H, Noda M and Nagasawa T: Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 25:977–988. 2006.
286	Ishida Y, Kimura A, Kuninaka Y, Inui M, Matsushima K, Mukaida N and Kondo T: Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing. J Clin Invest. 122:711–721. 2012.
287	Jiang Z, Li Y, Ji X, Tang Y, Yu H, Ding L, Yu M, Cui Q, Zhang M, Ma Y and Li M: Protein profiling identified key chemokines that regulate the maintenance of human pluripotent stem cells. Sci Rep. 7:145102017.
288	Bajetto A, Bonavia R, Barbero S, Florio T and Schettini G: Chemokines and their receptors in the central nervous system. Front Neuroendocrinol. 22:147–184. 2001.
289	Tiihonen J, Koskuvi M, Lähteenvuo M, Trontti K, Ojansuu I, Vaurio O, Cannon TD, Lönnqvist J, Therman S, Suvisaari J, et al: Molecular signaling pathways underlying schizophrenia. Schizophr Res. 232:33–41. 2021.
290	Simon IA, Bjørn-Yoshimoto WE, Harpsøe K, Iliadis S, Svensson B, Jensen AA and Gloriam DE: Ligand selectivity hotspots in serotonin GPCRs. Trends Pharmacol Sci. 44:978–990. 2023.
291	Littlepage-Saunders M, Hochstein MJ, Chang DS and Johnson KA: G protein-coupled receptor modulation of striatal dopamine transmission: Implications for psychoactive drug effects. Br J Pharmacol. May 31–2023. View Article : Google Scholar : Epub ahead of print.
292	Valencia M, Medina R, Calixto E and Rodríguez N: Cerebral, psychosocial, family functioning and disability of persons with schizophrenia. Neuropsychiat Dis Treat. 18:2069–2082. 2022.
293	Krogmann A, Peters L, Von Hardenberg L, Bödeker K, Nöhles VB and Correll CU: Keeping up with the therapeutic advances in schizophrenia: A review of novel and emerging pharmacological entities. CNS Spectrums. 24:38–69. 2019.
294	Borroto-Escuela DO, Carlsson J, Ambrogini P, Narváez M, Wydra K, Tarakanov AO, Li X, Millón C, Ferraro L, Cuppini R, et al: Understanding the role of GPCR heteroreceptor complexes in modulating the brain networks in health and disease. Front Cell Neurosci. 11:372017.
295	Yamamoto K and Hornykiewicz O: Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 28:913–922. 2004.
296	Newell KA, Zavitsanou K, Jew SK and Huang XF: Alterations of muscarinic and GABA receptor binding in the posterior cingulate cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 31:225–233. 2007.
297	Erskine D, Taylor JP, Bakker G, Brown AJH, Tasker T and Nathan PJ: Cholinergic muscarinic M(1) and M(4) receptors as therapeutic targets for cognitive, behavioural, and psychological symptoms in psychiatric and neurological disorders. Drug Discov Today. 24:2307–2314. 2019.
298	Krystal JH, Abi-Saab W, Perry E, D'Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L and Breier A: Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl). 179:303–309. 2005.
299	Yasuno F, Suhara T, Ichimiya T, Takano A, Ando T and Okubo Y: Decreased 5-HT1A receptor binding in amygdala of schizophrenia. Biol Psychiatry. 55:439–444. 2004.
300	Rasmussen H, Frokjaer VG, Hilker RW, Madsen J, Anhøj S, Oranje B, Pinborg LH, Glenthøj B and Knudsen GM: Low frontal serotonin 2A receptor binding is a state marker for schizophrenia? Eur Neuropsychopharmacol. 26:1248–1250. 2016.
301	Nikiforuk A: Serotonergic and cholinergic strategies as potential targets for the treatment of schizophrenia. Curr Pharm Des. 22:2093–2116. 2016.
302	Fatemi SH, Folsom TD and Thuras PD: Deficits in GABA(B) receptor system in schizophrenia and mood disorders: A postmortem study. Schizophr Res. 128:37–43. 2011.
303	Correll CU: Current treatment options and emerging agents for schizophrenia. J Clin Psychiatry. 81:MS19053BR3C2020.

January-2024
Volume 53 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

Recommend to Library

Journal Metrics
Impact Factor: 5.4
Ranked Medicine Research and Experimental
(total number of cites)
CiteScore: 10.7
CiteScore Rank: Q1: #35/328 Biochemistry, Genetics and Molecular Biology
Source Normalized Impact per Paper (SNIP): 0.994
SCImago Journal Rank (SJR): 0.922

GPCR	Associated signaling	Implications in SZ	(Refs.)
Type D₁ (D₁ and D₅)	Gα_q/G_s	Elevated mRNA levels of D₁ receptors in the temporal and parietal cortex	(93)
Type D₂ (D_2-4)	Gα_i/G_o	Overexpression in the striatum leads to deficits in inhibitory neurotransmission and dopamine sensitivity in the prefrontal cortex	(92)
Adrenergic (α₁, β_1-3) Adrenergic (α₂, β₂, β₃)	Gα_q/G_s Gα_i	Positive symptoms are exacerbated by selective and indirect norepinephrine receptor agonists, while antagonists decrease symptoms	(295)
Muscarinic (M₁, M₃, M₅) Muscarinic (M₂, M₄)	Gα_q/G₁₁ Gα_i/G_o	Transcriptional and proteomic alterations in M₁ and M₄ receptors in the hippocampus and prefrontal, frontal and cingulate cortex	(296,297)
mGlu (mGluR1, mGluR5)	Gα_q/G_s	Overexpression of mGluR1 in the prefrontal cortex of patients	(152)
mGlu (mGluR2-4 and 6-8)	Gα_i/G_o	mGluR2/3 may serve a role in working memory associated with NMDA receptor hypofunction	(82,298)
Serotonergic (5-HT₁, 5-HT₅)	Gα_i/G_o	Decreased binding of 5HT to the 5-HT_1A receptor in the amygdala of patients	(299)
Serotonergic (5-HT₂)	Gα_q	Alterations in frontal cortical 5-HT_2A receptor binding and decreased receptor density in the brain of patients	(300)
Serotonergic (5-HT₄, 5-HT₆, 5-HT₇)	Gα_s	5-HT₇ in the human brain and reduced mRNA levels in the prefrontal cortex of patients	(301)
GABA_B metabotropic (GBR2)	Gα_i/G_βγ	GABA_BR1 (6p21.3) and GABA_BR2 (5q34) gene loci are SZ susceptibility loci	(302)

International Journal
of Molecular
Medicine