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Determining the role of microRNAs in psychiatric disorders

Key Points

  • Accumulating studies have revealed that patients with psychiatric disorders have altered microRNA (miRNA) expression profiles in the circulation and in relevant brain tissues. Furthermore, animal studies have shown that manipulating the levels of particular miRNAs in the brain can alter behaviour.

  • The expression levels of some miRNAs change following certain behavioural or pharmacological challenges, thus facilitating a subsequent change in the expression of target genes, which are putatively needed in order to direct certain behavioural outcomes. It is also possible that miRNAs can serve as 'buffers' to keep levels of their protein targets stable and to avoid them being upregulated to pathological levels in response to a challenge.

  • We discuss the pros and cons of the available molecular, biochemical, cellular and behavioural experimental approaches in both humans and rodents that are used for studying the role of miRNAs in psychiatric disorders. We also highlight example studies.

  • We discuss future directions for studies examining the role of miRNAs in psychiatric disorders, emphasizing the importance of studies on both sexes, the need for utilizing proteomics analysis methods, the need for spatiotemporal expression maps of endogenous miRNAs in the developing and adult brain, and the need for testing miRNAs in specific cell types, circuits and subcellular fractions.

  • Shedding light on the role of miRNAs in psychiatric disorders could lead to a better understanding of the molecular pathways that are disrupted in these disorders and possibly promote the much needed development of new therapeutic and diagnostic approaches.

Abstract

Recent studies have revealed that patients with psychiatric disorders have altered microRNA (miRNA) expression profiles in the circulation and brain. Furthermore, animal studies have shown that manipulating the levels of particular miRNAs in the brain can alter behaviour. Here, we review recent studies in humans, animal models, cellular systems and bioinformatics that have advanced our understanding of the contribution of brain miRNAs to the regulation of behaviour in the context of psychiatric conditions. These studies highlight the potential of miRNA levels to be used in the diagnosis of psychiatric disorders and suggest that brain miRNAs could become novel treatment targets for psychiatric disorders.

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Figure 1: A working hypothesis of the aetiology of psychiatric disorders.
Figure 2: MicroRNA-related genetic variations that may be associated with psychiatric disorders.
Figure 3: Approaches for manipulating specific brain microRNA expression levels and function.
Figure 4: Using microRNA biology in psychiatry for diagnostics or therapeutics.

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Acknowledgements

The authors acknowledge those whose work they could not cite owing to lack of space. They thank S. Haramati-Rodrig and O. Furman for their critical scientific editing; N. Volk for assisting with Box 1; and E. Geron, Y. Kuperman, Y. Ben-Efraim and N. Volk for reading the Review and providing comments. The authors also thank E. Hornstein for discussions and insights. A.C.'s work is supported by an FP7 grant from the European Research Council (260463); the Max Planck Society — Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics; a research grant from the Israel Science Foundation (803/11); research support from Roberto and Renata Ruhman; the Nella and Leon Benoziyo Center for Neurological Diseases; the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation founded by Louis L. and Anita M. Perlman for research in the field of metabolism; the Adelis Foundation; Marc Besen and the Pratt Foundation; and the Irving I. Moskowitz Foundation.

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Correspondence to Orna Issler or Alon Chen.

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Glossary

Epigenetic mechanisms

Molecular mechanisms leading to changes in gene expression levels that are not due to variations in the DNA sequence.

Copy number variations

(CNVs). Genetic variations in which large areas in the genome are deleted or duplicated.

Single-nucleotide polymorphisms

(SNPs). Common genetic variations occurring in one base pair.

Seed match sequences

Short sequences within the 3′untranslated region of a target gene (seed match sequence) that are complementary to sequences within a microRNA (the seed sequence); the seed and seed match sequences direct the specificity of the miRNA–target gene interactions.

Genome-wide association study

(GWAS). A study that correlates common genetic variations in the entire human genome with a specific disease.

AGO2 immunoprecipitation

A method for co-isolation of mRNA and microRNA (miRNA) from cells or tissues that are associated with the Argonaute 2 (AGO2) protein; it allows 'capturing' of active miRNA–target (mRNA) interactions under specific experimental conditions.

Transgenerational effects

Phenotype changes in the offspring that are caused by parental exposure to environmental factors.

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Issler, O., Chen, A. Determining the role of microRNAs in psychiatric disorders. Nat Rev Neurosci 16, 201–212 (2015). https://doi.org/10.1038/nrn3879

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