Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinosito1-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CM region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CM region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1 alpha (protein phosphase 1 alpha)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CM region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CM LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.