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Background  Proper neuronal function requires tight control of gene dosage, and failure of this process underlies the pathogenesis of multiple neuropsychiatric disorders. The  SHANK3  gene encoding core scaffolding proteins at glutamatergic postsynapse is a typical dosage-sensitive gene, both deletions and duplications of which are associated with Phelan-McDermid syndrome, autism spectrum disorders, bipolar disorder, intellectual disability, or schizophrenia. However, the regulatory mechanism of  SHANK3  expression in neurons itself is poorly understood.    Results  Here we show post-transcriptional regulation of  SHANK3  expression by three microRNAs (miRNAs), miR-7, miR-34a, and miR-504. Notably, the expression profiles of these miRNAs were previously shown to be altered in some neuropsychiatric disorders which are also associated with  SHANK3  dosage changes. These miRNAs regulated the expression of  SHANK3  and other genes encoding actin-related proteins that interact with Shank3, through direct binding sites in the 3′ untranslated region (UTR). Moreover, overexpression or inhibition of miR-7 and miR-504 affected the dendritic spines of the cultured hippocampal neurons in a Shank3-dependent manner. We further characterized miR-504 as it showed the most significant effect on both  SHANK3  expression and dendritic spines among the three miRNAs. Lentivirus-mediated overexpression of miR-504, which mimics its reported expression change in postmortem brain tissues of bipolar disorder, decreased endogenous Shank3 protein in cultured hippocampal neurons. We also revealed that miR-504 is expressed in the cortical and hippocampal regions of human and mouse brains.    Conclusions  Our study provides new insight into the miRNA-mediated regulation of  SHANK3  expression, and its potential implication in multiple neuropsychiatric disorders associated with altered  SHANK3  and miRNA expression profiles.    Electronic supplementary material  The online version of this article (doi:10.1186/s13041-015-0165-3) contains supplementary material, which is available to authorized users.

Post-transcriptional regulation of SHANK3 expression by microRNAs related to multiple neuropsychiatric disorders