miR-936 is Increased in Schizophrenia and Inhibits Neural Development and AMPA Receptor-Mediated Synaptic Transmission.

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression and play important roles in the development and function of synapses. miR-936 is a primate-specific miRNA increased in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. The significance of miR-936 increase to schizophrenia is unknown. Here, 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 neurons derived from human induced pluripotent stem cells (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. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2021.