Abstract
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.