The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder

SUMMARY Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a substantial portion of genetic risk as well as their clinical manifestations. This raises a fundamental question of whether, and how, common neurobiological pathways translate their shared polygenic risks into shared clinical manifestations. The present study shows the miR-124-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disorders. We discovered upregulation of miR-124 in biopsied neuronal cells and postmortem prefrontal cortex from both SZ and BP patients, implying its role not only as a biomarker, but also as a pathophysiological mediator. Intriguingly, the upregulation is associated with the polygenic risks shared between these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124 in the medial prefrontal cortex, which includes brain regions homologous to sub-regions of the human prefrontal cortex. We demonstrated that upregulation of miR-124 increases GRIA2-lacking calcium permeable-AMPARs and perturbs AMPAR-mediated excitatory synaptic transmission, leading to deficits in the behavioral dimensions shared between SZ and BP.