Molecular Psychiatry

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Little things on which happiness depends: microRNAs as novel therapeutic targets for the treatment of anxiety and depression

R M O'Connor, T G Dinan and J F Cryan

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Figure 1.

Biogenesis of microRNAs (miRNAs). miRNA genes are transcribed by RNA polymerase II producing a pri-miRNA. The pri-miRNA is then processed by Drosha to produce hairpin structures called pre-miRNAs. Pre-miRNAs are then exported from the nucleus to the cytoplasm via the exportin5-Ran complex. In the cytoplasm, they are further processed by Dicer producing the mature miRNA. The mature miRNA is then incorporated into the RNA-induced silencing complex (RISC). The miRNA-RISC complex is then able to repress translation in a sequence-specific manner either through degradation of the target mRNA or by blocking access of the cells' translational machinery to the mRNA.

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Figure 2.

Common experimental strategies in the search for miRNAs that have the potential to serve as therapeutic targets for depression and anxiety disorders. Differential microRNA expression can be identified from different experimental groups (for example, non-disease state versus disease state or non-treated versus treated) obtained from patients, pre-clinical models or originate from an in vitro source. A micorarray can be used to assess differences in the levels of a large number of different miRNAs between the different experimental groups. The results obtained will then need to be verified using quantitative reverse transcriptase PCR (qRT-PCR). Alternatively, a researcher may chose to use bioinformatic algorithms to prioritise a single or a particular set of miRNAs for analysis via qRT-PCR (for example, based on predicted miRNA effectors of a gene of interest (GOI)). The miRNAs whose differential expression between groups which have been verified through qRT-PCR, can then be analysed using in vitro assays to confirm target predictions or move directly to pre-clinical models to predict potential antidepressant or anxiolytic behaviour. From this, individual miRNAs can be prioritised for follow-up work to confirm their potential therapeutic potential.

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