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The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder
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DOI：10.1016/j.neuron.2022.10.031.png)
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Abstract
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Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a sub-stantial 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 clin-ical manifestations. This study shows the miR-124-3p-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disor-ders. We discovered the upregulation of miR-124-3p in neuronal cells and the postmortem prefrontal cortex from both SZ and BP patients. Intriguingly, the upregulation is associated with the polygenic risks shared be-tween these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124-3p in the medial prefrontal cortex. We demonstrated that the upregulation of miR-124-3p increases GRIA2-lacking calcium-permeable AMPARs and perturbs AMPAR-mediated excitatory synaptic transmis-sion, leading to deficits in the behavioral dimensions shared between SZ and BP.
Keywords:
MAJOR PSYCHIATRIC-DISORDERS
PREFRONTAL CORTEX
GENE-EXPRESSION
MOLECULAR NEUROPATHOLOGY
GENOTYPE IMPUTATION
MICRORNA EXPRESSION
NEURAL PROGENITORS
PYRAMIDAL NEURONS
STEM-CELLS
AMPA
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