| Abstract: | 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 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 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 CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)–P-Rex1–Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.Deficits in social interaction and communication skills and repetitive behavior/restricted interests have been demonstrated in people diagnosed with autism spectrum disorders (ASDs) (1). Several studies have documented impairments of social recognition [e.g., such as deficits in recognizing unfamiliar faces (2)] and in behavioral flexibility [e.g., impaired reversal learning and difficulties in error correction (3, 4)] in autistic people. However, the neurobiological mechanism responsible for the symptoms of ASDs, and especially for the deficit in social recognition, is little known.Recent genetic studies have identified a large number of candidate genes for ASDs (5, 6), including many that code for synaptic proteins. Synaptic dysfunction may play a critical role in ASDs (7).Here we have identified a new autism-associated gene, Prex1, that codes for P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1), a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF). This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1−/−) exhibited Rac-dependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone. However, the role of P-Rex1 in regulating synaptic function and related behaviors remains unknown.In addition to identifying an association between PREX1 and autism in humans, we demonstrate that genetic disruption of P-Rex1 in mice leads to autism-like social behavior and to other features known to be associated with ASDs. Electrophysiological studies revealed a specific impairment of NMDA receptor (NMDAR)-dependent long-term depression (LTD) at Schaffer collateral– cornus ammonis region 1 (SC–CA1) synapses. Furthermore, these defects were associated with dysfunction in NMDA-induced AMPA receptor (AMPAR) endocytosis, because of defective PP1α (serine/threonine protein phosphase 1α)–P-Rex1–Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling, and correcting the latter rectified the social recognition deficit of Prex1−/− mice. Thus, we have elucidated a synaptic mechanism underlying the deficit in social recognition induced by P-Rex1 disruption and the cognitive dysfunction associated with ASDs. |
