Schizophrenia is a severe psychiatric disorder that has been found to have a lifetime prevalence of ~1% in a number of population studies (1–3). The condition is characterized by impaired cognition, positive psychotic symptoms, including hallucinations, delusions and disorganized behavior, and negative symptoms, such as social withdrawal and apathy (2). Schizophrenia is a ‘complex genetic disease’, with an etiology involving multiple genetic and environmental factors. The genetic contribution is significant, since schizophrenia has been shown to have a heritability risk of ~80%, with the risk decreasing by ~50% for each degree of family relation (3).

miRNAs are a class of small RNAs found only in eukaryotes, which were first identified less than two decades ago. Modulation of gene expression does not rely solely on regulatory proteins. miRNAs are single-stranded RNA molecules, consisting of 21–23 nucleotides, that are not translated into proteins, but are key to the complex cell machinery responsible for gene expression (4). A previous study estimated that one third of human genes are directly targeted by miRNAs (5). In an attempt to clone the gene responsible for the lin-4 phenotype in roundworms, Lee et al identified miRNAs for the first time as small non-coding RNA molecules (6). To date, 2,652 mature human miRNAs have been identified (www.mirbase.org; accessed 20, June 2013).

The biogenesis of miRNAs is initiated by transcription from intergenic or intron genomic regions into primary-miRNA molecules (pri-miRNAs). Pri-miRNAs are cleaved inside the nucleus by the components of the microprocessor complex, consisting of Drosha and DGCR8, to generate RNA hairpins, known as precursor-miRNA molecules (pre-miRNAs). Pre-miRNA is exported into the cytoplasm and is further cleaved by the RNaseIII enzyme, Dicer; therefore, a duplex of two miRNA strands is formed. Next, the miRNA duplex is unwound and one of the strands is incorporated into a large miRNA-induced silencing complex, which participates in the detection and binding to the 3′-untranslated region of messenger RNAs (mRNAs). As a result, translation is inhibited. However, the underlying mechanisms are yet to be fully understood (Fig. 1) (7).

A hemizygous deletion of a 1.5–3-Mb region of chromosome 22 can lead to the 22q11 deletion syndrome (22q11DS), which is characterized by multiple physical and psychiatric abnormalities. A previous study determined that ~30% of 22q11DS patients may develop schizophrenia (8). miR-25 and miR-185 are regulators of the sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA2), which is responsible for loading Ca²⁺ into the endoplasmic reticulum. Earls et al found that miR-25 and miR-185 were depleted in mouse models of 22q11DS and restoration of these miRNAs to presynaptic neurons rescued the long-term potentiation of DGCR8^+/− mice (1). The authors concluded that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.

The intricate architecture of the nervous system and the ability of the neurons for postsynaptic remodeling requires the coordination of complex intracellular networks consisting of molecular signal transduction systems. Due to the abundance of neural networks, gene variants are able to cause system dysfunctions, manifesting as associated neurobehavioral syndromes. Previous studies revealed that post-transcriptional gene regulation by miRNA is an important factor shaping the topography of the neural networks. Over half of miRNAs identified have been shown to be highly or exclusively expressed in the brain, a number of which have been implicated in important aspects of neuronal function (9). miR-124 and miR-9 play a crucial role in neurogenesis; overexpression of these miRNAs decreases the number of astrocytes, whereas inhibition of these miRNAs reduces the number of neurons (10). miR-134 was found to regulate the size of dendritic spines and enrich the synapse dendritic region of rat hippocampal neurons (11). In addition, miR-134 regulates the translation of Limk1, which is a protein kinase that affects dendritic spine morphology via the regulation of actin filaments (5).

miRNA has received increasing attention in genetic studies of schizophrenia. A number of studies support the hypothesis that miRNA plays an important role not only in human brain development, but also in brain diseases (12–16). Hunsberger et al hypothesized that miRNA may serve as a unifying link among the structural developmental anomalies, neurotransmitter alterations and response to treatment in schizophrenia (17). The schizophrenia-associated miRNAs are summarized in Table I.

Alterations in the sequence of certain miRNAs leads to the alteration of gene regulation, which contributes to the development of a psychiatric disorder. Perkins et al compared the expression of 264 miRNAs from the prefrontal cortex of patients diagnosed with schizophrenia and 21 individuals not suffering from a psychiatric illness, used as controls (18). Using a custom-made miRNA microarray, the authors identified that the expression of 15 miRNAs decreased and the expression of one miRNA increased in the prefrontal cortex of the schizophrenia patients, when compared with the control individuals.

In addition, Guo et al demonstrated that miR-195 is involved in a complex regulatory network, which affects the signaling pathways considered to be significant in the development of schizophrenia (19).

The gene encoding miR-346 is located in the intron of the glutamate receptor ionotropic δ1 (GRID1) gene, which is known to be involved in schizophrenia susceptibility (5). Using quantitative polymerase chain reaction, Zhu et al detected the expression levels of miR-346 and GRID1 in brain RNA samples of 35 patients with schizophrenia and 34 controls, obtained from the Stanley Medical Research Institute (Chevy Chase, MD, USA) (3). The expression levels of miR-346 and GRID1 were found to be lower in the schizophrenia patients compared with the controls.

In a study of the Chinese population, Xu et al described a potentially functional variant that affected pre-miR-30e and was closely associated with schizophrenia (28). The variant affected the predicted structure and the release of pre-miRNA, as well as the accuracy of the mature miRNA. Despite the samples being obtained from the peripheral blood, the findings of Xu et al were comparable to the observations of Perkins et al (18), who detected an increase in the expression level of miR-30e in the prefrontal cortex of patients with schizophrenia.

Smrt et al demonstrated that miR-137 serves as a regulator of adult neural stem cell maturation and migration to the subventricular zone, located around the lateral ventricles, and the subgranular zone of the hippocampus (35). In addition, miR-137 was shown to be highly associated (P=1.6×10⁻¹¹) with schizophrenia in one of the largest genome-wide association studies (36). Since miRNAs are crucial regulators of gene expression, important genetic mechanisms may contribute to the phenotypic heterogeneity. Lett et al made demographics for age-at-onset samples, as well as healthy controls, and their findings indicated that miR-137 plays a considerable role in the variation in phenotypes that is believed to have an important role in clinical outcome and treatment response (20). The authors concluded that the effects of miR-137 on the phenotypic heterogeneity of schizophrenia may occur via neurodevelopmental gene networks. These observations may provide a model for the role of miRNAs in the phenotypic heterogeneity of psychiatric disorders.