Munc18-1 promotes or inhibits the assembly of the SNARE complex primarily by combining with syntaxin-1 (Habc domain; N-terminal short peptide) in the ‘open’ and ‘closed’ conformations (17). Munc18-1 regulates vesicle fusion by interacting with the SNARE complex, affects the number of vesicles released and the supply of vesicles, and participates in the transmission of various neurotransmitters, including dopamine, glutamate and γ-aminobutyric acid (GABA) (Fig. 1) (18,19).

Previous studies have demonstrated that the N-terminal peptide and Habc domain of syntaxin-1 serve an important role in synaptic vesicle fusion. The N-terminal peptide is essential for vesicle fusion itself, whilst the Habc domain regulates this fusion by forming a closed syntaxin-1 conformation (20,21). The current hypothesis is that Munc18-1 and syntaxin-1 have several binding modes: i) Munc18-1 binds to syntaxin-1 (via the Habc domain) in a ‘closed’ conformation, stabilizing the conformation of syntaxin-1 and inhibiting the assembly of the SNARE complex (16); ii) Munc18-1 combined with ‘closed’ conformation syntaxin-1 serves as a template for SNARE assembly, with Munc13-1 helping to open the syntaxin-1 ‘closed’ conformation. Munc13-1 Bridges synaptic vesicles and presynaptic membrane fusion, and Munc18-1 and Munc13-1 coordinate the assembly of the T-SNARE complex together in an NSF-SNAP resistant manner (22); and iii) Munc18-1 combined with the ‘open’ conformation ofsyntaxin-1 (N-terminal short peptide) initiates and stimulates SNARE-mediated membrane fusion (16). The regulatory mechanism of Munc18-1 is complex, involving promotion and inhibition of SNARE assembly; however, the promotion process is the more dominant of the two.

Munc18-1 can function to regulate brain-derived neurotrophic factors, participate in the development of synapses and affect cognitive functions (23,24). Synaptic plasticity is the basic process responsible for learning and memory (25). Previous studies have determined that the expression of Munc18-1 was decreased in the hippocampus of STXBP1 heterozygous knockout mice. This impaired synaptic plasticity, synaptic vesicle release rate and vesicle pool production, leading to impaired learning and memory (26–28). Activation of the diacylglycerol/protein kinase C (PKC) pathway can enhance neuronal synaptic transmission (29,30). In addition to the phosphorylation of Munc18-1, which transfers synaptic vesicles to active regions, the PKC pathway further accelerates the assembly of the SNARE complex (31,32). Synaptotagmin-1 is a synaptic-associated protein, the phosphorylation of which is an important step in the PKC pathway of synaptic transmission (33). Together with Munc18-1 phosphorylation, they represent an important aspect of synaptic plasticity, enhancing synaptic transmission and promoting neurotransmitter release (34,35).

The functional destruction of Munc18-1 affects the development of the cerebral cortex, which may cause neurodevelopmental disorders by affecting brain-derived neurotrophic factor and the downstream tropomyosin receptor kinase B pathway (36). While the functions of the exocytotic proteins SNARE and Munc18-1 have garnered increasing attention, studies have demonstrated that Munc18-1 promotes insulin secretion by interacting with SNARE, and the decline of its expression leads to insulin secretion disorders (37,38). Thyroid hormone is very important for normal brain development. Previous studies have determined that in mice with mild spatial cognitive impairment, the spatial learning and memory of old and middle-aged mice decreases. Additionally, the expression of serum thyroxine is decreased in these animals, which increases Munc18-1 levels, demonstrating a negative correlation and indicating that Munc18-1 negatively regulates the role of thyroxine in brain development (39–41).

Epileptic encephalopathy is a severe brain dysfunction with poor prognosis that is commonly observed in infants and children, and is often characterized by frequent seizures, intellectual disability and dyskinesia (51). The etiology of epileptic encephalopathy is not completely understood, and it has been reported that ~70% of epileptic encephalopathy cases are associated with genetic factors (52,53). An increasing number of studies have reported that STXBP1exhibitsmultiple mutation types in severe epileptic encephalopathy, including missense and splicing mutations, which lead to single protein insufficient ploidy, impaired protein stability, unbalanced cortical excitement, impaired synaptic plasticity and GABA-ergic transmission barriers that adversely affect learning and memory (28,43). The treatment of epileptic encephalopathy is challenging. However, studies have reported that drugs such as Keppra and adreno-cortico-tropic-hormone can prevent epilepsy to a certain extent, exerting no significant effect on other clinical symptoms, such as psychomotor disability and cognitive dysfunction (54–57).

Ohtahara syndrome, also known as epileptic encephalopathy in early infants, is a severe seizure related to stunting and mental disability. Its other neurological characteristics include autism spectrum disorder and dyskinesia (14). STXBP1 is the pathogenic gene of Ohtahara syndrome. Saitsu et al (58) identified that STXBP1 was mutated in children with this syndrome in 2008. With research on genetic diagnosis, an increasing number of studies have identified gene mutations in Ohtahara syndrome (59,60). A previous study demonstrated that the clinical manifestations in children <3 months were accompanied with tonic spasm, and the electroencephalograms of most children exhibited burst suppression in Ohtahara syndrome (61). The main clinical manifestations of West syndrome include nodding spasm, high irregularities in electroencephalograms and severe intellectual disability. Since Otsuka et al (62) first reported the STXBP1 mutation in West syndrome in 2010, following studies then identified STXBP1 nonsense and splice site mutations through clinical studies (63). In addition, STXBP1 mutations were identified in Dravet syndrome and Lennox-Gastaut syndrome, although evidence of these mutations in Ohtahara syndrome is not sufficient (64,65). Rett syndrome (RTT) is a neurodevelopmental disorder typically caused by mutations of methyl-CpG binding protein 2 (MECP2). However, Yuge et al (66) reported in 2018 that a STXBP1 mutation was detected in a case diagnosed with RTT. Moreover, a 9-year-old female with RTT and severe cognitive impairment exhibited no MECP2 mutation, but a STXBP1mutation was identified. MECP2 gene mutations result in the decrease of glutamate and gamma-aminobutyric acid receptor densities (17). It is hypothesized that deficits in synaptic plasticity may, to some extent, indicate an association between MECP2 and the pathogenicity of STXBP1 mutations (17).

Autism is a common neurodevelopmental disorder with a high disability rate and strong genetic basis (67). At present, while almost all patients with STXBP1 mutations exhibit certain clinical phenotypes, including seizures and mental disabilities, ~20% have autism and can demonstrate increased aggressive behavior (68,69). A study by Dachtler et al (45) used a synaptic adhesion protein α-neurexin II-deficient mouse model of autism, and through protein quantitative analysis, detemined that Munc18-1 encoded by STXBP1 was significantly reduced in the hippocampus of mice. Synaptic adhesion proteins serve a key role in the formation and maintenance of synapses, and are involved in mediating synaptic plasticity (70). Decreased expression of Munc18-1 regulates the expression of α-neurexin II, impairs synaptic plasticity and participates in the occurrence of autism (71). In a mouse model of heterozygous STXBP1 knockout, it was revealed that the number of vesicles in the synaptic active region was reduced, and glutamatergic and GABA-ergic transmission were impaired. These mice demonstrated increased anxiety and impaired emotional learning (72). In addition, Miyamoto et al (73) reported that the normalization of excitatory synaptic transmission in STXBP1 knockout mice, which exhibit various degrees of cognitive impairment and aggressiveness, improved Munc18-1 haploid deficiency-related aggression. It is speculated that Munc18-1 may be involved in the clinical phenotype of autism, potentially providing novel treatment methods.

SCZ is a severe mental disorder with unclear causes. The main hypotheses suggest that it is mediated by overactive dopamine activity, 5-hydroxytryptamine and norepinephrine neural pathway dysfunction, excitatory amino acid dysfunction and the neuropeptide hypothesis. Neuropeptide protein is involved in the process of neurodevelopment, and low expression is involved in SCZ through the release of glutamate and γ-aminobutyric acid) (74). A proteomic analysis of the brain tissue of patients with SCZ by Behan et al (46) determined that Munc18-1 was highly expressed. Compared with patients who did not use anti-SCZ drugs, Munc18-1expression in patients who used these drugs decreased. Additionally, in a mouse model of SCZ utilized by Urigüen et al (75), a high expression of Munc18-1 was identified in the gray matter of the brain. Similarly, a high expression of Munc18-1 was detected in STXBP1 transgenic mice, which exhibited symptoms of SCZ, decreased expressions of dopamine receptors, decreased expressions of membrane transporters and decreased brain gray matter volume (75). Munc18-1 participates in the pathogenesis of SCZ by regulating excitatory neurotransmitters; however, the cause and mechanism of associated brain volume reduction is unclear.

Parkinsons disease is a degenerative disease of the nervous system. Previous studies have demonstrated that the abnormal expression of α-synuclein and self-replication aggregation serve a key role in the degenerative changes of Parkinsons disease neurons (76,77). Munc18-1 serves other biological functions in addition to regulating neurotransmitter transmission. For example, Lanoue et al (78) revealed that Munc18-1 participates in various neurodegenerative diseases, including Parkinsons disease, by controlling the self-replication and aggregation of α-synuclein. Neurodevelopment in epileptic encephalopathy may also be affected by synuclein (78). The physiological functions of α-synuclein are complex; α-synuclein self-replication and aggregation inhibit exocytosis, affect vesicle secretion and regulate synaptic plasticity (76,79). A previous study revealed that Munc18-1 acts as a chaperone to regulate the replication and aggregation of α-synuclein, the decreased expression of Munc18-1 increases the aggregation tendency of α-synuclein, while the increased expression of Munc18-1 reverses this affect (80). At present, the specific pathways underlying the Munc18-1-associated regulation of α-synuclein are unclear, and further research is required to further understand and effectively treat Parkinsons disease.

AD is a progressive neurodegenerative disorder with an insidious onset. Its etiology includes the deposition of abnormal amyloid β extracellular plaques and intracellular neurofibrillary tangles containing hyperphosphorylated Tau protein, which lead to impaired synaptic plasticity (81). Previous studies have demonstrated that at the GABA-ergic presynaptic inhibition terminal, the expression of the Munc18-1 long splice variant is closely associated with cognitive function. Furthermore, the deletion of the Munc18-1 long splice variant increases the risk of AD (47,82). In a study assessing the effect of pomegranate on an AD mouse model, it was determined that pomegranate can enhance synaptic plasticity by increasing the expression of Munc18-1, SNAP25 and synaptophysin, improving spatial learning impairment in mice (83). Additionally, a study has determined that when comparing the brain tissue of healthy individuals and deceased patients with AD of the same age, brain tissue following AD-associated death is rich in highly phosphorylated Tau protein and Munc18-1 is abnormally expressed (84). The current treatment methods used for patients with AD remain poor, and further understanding of Munc18-1 may provide a novel target.

The most common type of white matter injury is demyelination, which includes myelin loss and axonal abnormalities (85). MS is an autoimmune disease characterized by the inflammatory demyelination of white matter in the central nervous system (86). A previous study reported that in a murine model of multiple sclerosis, the expression of Munc18-1 and axon structural protein α-internexin increases, and the expression of glutamate decarboxylase decreases, mediating immunity to myelin damage (48). An increased expression of α-internexin, axon disintegration, the Munc18-1 regulation of glutamatergic transmission and glutamate excitotoxicity further increase axon damage (87). However, there are few studies that assessMunc18-1 in MS and the specific underlying pathogenic mechanism remains unknown.

Duchenne muscular dystrophy is a disease that affects the neuromuscular system. Progressive skeletal muscle atrophy is the main complication, and developmental cognitive deficits and behavioral abnormalities are its main clinical features (88). Murphy et al (49) performed proteomics on the brain tissue of mice with Duchenne muscular dystrophy, the results of which revealed that the expression of Munc18-1 was significantly decreased. A further study revealed that the expression of Munc18-1 was significantly decreased in the brains of children with neuronal ceroid lipofuscinosis (50). These studies indicate that Munc18-1 may be involved in the pathogenesis of Duchenne muscular dystrophy and neurodegenerative lysosomal diseases. Combined with the characteristics of these diseases, impaired synaptic plasticity and neurodevelopmental pathways serve an important role in these diseases. Munc18-1 may participate in the pathogenesis of disease by regulating synaptic plasticity and neurodevelopment; however there are few related studies to confirm this, and the specific underlying mechanisms require further exploration.