Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior
Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior
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突触 P-Rex1 信号调节海马长期抑郁和自闭症样社会行为
DOI：
10.1073/pnas.1512913112
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发表时间：
2015-12-15
影响因子：
11.1
通讯作者：
Zhang, Dai
中科院分区：
文献类型：
--
作者：
Li, Jun;Chai, Anping;Zhang, Dai
在自闭症患者中发现了社会行为和行为灵活性的障碍。然而，可能导致这些症状的遗传机制尚不清楚。在这里，我们确定了一个以前未报道的自闭症相关基因，调节突触可塑性。缺乏这种基因的小鼠表现出AMPA受体内吞作用和突触抑制的缺陷，因为突触后信号通路的阻断，导致自闭症样的社会识别缺陷和行为障碍。这些发现为社会识别行为的机制提供了新的见解，并表明突触抑郁相关的信号通路可能代表了治疗自闭症谱系障碍等社会识别缺陷障碍的新治疗靶点。自闭症谱系障碍（Autism spectrum disorders，ASD）是一组与突触功能障碍相关的高度遗传性精神障碍，但其潜在的细胞和分子机制仍有待阐明。本文报道中国汉族人群孤独症与P-Rex 1基因的遗传变异和拷贝数缺失有关。小鼠海马CA 1区P-Rex 1基因缺失或敲低导致自闭症样社会行为，该行为通过改变突触后PP 1 α（蛋白磷酸酶1α）-P-Rex 1-Rac 1（Ras相关C3肉毒毒素底物1）信号通路介导的AMPA受体内吞作用与CA 1区长期抑郁（LTD）缺陷特异性相关。在CA 1区的LTD的救援显着减轻自闭症样的社会行为。总之，我们的研究结果表明，P-Rex 1信号在CA 1 LTD中起着至关重要的作用，对社会行为和认知功能至关重要，并为ASD的病因学提供了新的见解。
Significance Impairments in social behavior and behavioral flexibility have been found in autistic people. However, the genetic mechanism that may contribute to these symptoms is unknown. Here we identified a previously unreported autism-associated gene that regulates synaptic plasticity. The mice lacking this gene exhibit deficits in AMPA receptor endocytosis and synaptic depression because of the blockade of a postsynaptic signaling pathway, leading to autism-like social recognition deficit and behavioral inflexibility. These findings provide new insights into the mechanisms underlying social recognition behavior and suggest that the synaptic depression-related signaling pathway might represent a new therapeutic target for treatment of social recognition deficit disorders such as autism spectrum disorders. 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.