Characterizing the Function of miRNAs in Neural Development, Synaptic Plasticity and Schizophrenia.

National Institute Of Mental Health

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Abstract

Numerous studies have shown that the brains of people with schizophrenia have anomalous gene expression which may arise from dysregulation of gene expression. MicroRNAs (miRNAs) are small non-coding RNAs that regulate translation. They bind to mRNAs, usually at the 3 untranslated region, to suppress translation or destabilize mRNAs. miRNAs play a role in a variety of neuronal processes including the structure and function of synapses. Postmortem studies show that miRNAs in the DLPFC are altered in schizophrenia. It is possible that miRNAs are involved in neural maturation and synaptogenesis of the DLPFC and that miRNA alterations may contribute to the development of schizophrenia. Characterizing the functions of miRNAs altered in schizophrenia, therefore, may provide insights into the molecular mechanism of schizophrenia. We previously analyzed miRNA expression using next-generation sequencing in the postmortem DLPFC of individuals affected with schizophrenia. We found that miR-936 is increased in the DLPFC of individuals with schizophrenia using next-generation sequencing. This increase is likely caused by the disease rather than antipsychotics as there is no correlation between miR-936 expression and psychiatric medications. miR-936 is a primate-specific miRNA with a distinct developmental profile in the human DLPFC, which is low in toddlers and high in adolescents. During this reporting period, we validated miR-936s expression change in an independent cohort, examined the laminar and cell-type distribution patterns of miR-936 in the human DLPFC and its function in human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (iNs). We analyzed the effect of altered miRNA expression on the basic biophysical properties, miniature and evoked synaptic responses, and synapse number in these neurons. We show that miR-936 in the human DLPFC is enriched in cortical layer 2/3 and expressed in glutamatergic and GABAergic neurons. miR-936 is increased from layers 2 to 6 of the DLPFC in schizophrenia samples. In human iNs, miR-936 reduces the number of excitatory synapses, inhibits AMPA receptor-mediated synaptic transmission, and increases intrinsic excitability. These effects are mediated by its target gene TMOD2. These results indicate that miR-936 restricts the number of synapses and the strength of glutamatergic synaptic transmission by inhibiting TMOD2 expression. miR-936 upregulation in the DLPFC, therefore, can reduce glutamatergic synapses and weaken excitatory synaptic transmission, which underlie the synaptic pathology and hypofrontality in schizophrenia.