自闭症又称孤独症，是早期神经系统发育异常导致的精神障碍。因其遗传和病理机制不明，尚无有效干预手段。神经连接素Neuroligins（NLs）特异性表达于突触后膜，介导神经突触形成并调节突触传递，其多个家族蛋白的缺失或突变与自闭症密切相关，但其具体机制尚不明确。本项目以原代培养大鼠神经元及NL3基因敲除小鼠为模型发现NL3参与调控Akt/mTOR信号通路，影响蛋白合成及神经元树突发育。本项目追踪了其中具体信号级联方式，并发现了NL3的一个新相互作用因子MAGI2可能共同参与调节。本项目在前期数据支持下，拟继续从分子、细胞和脑区相关的行为学水平深入阐明NL3通过与MAGI2相互作用调控mTOR信号通路的具体分子机制，明确其功能上的细胞亚群特异性，评价其对神经元发育和神经突触传递以及脑区功能和行为学产生的影响，最后在自闭症模型小鼠上利用针对mTOR信号通路的新型药物探索对自闭症干预的有效手段。

Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and signaling processes. Genetic defects in NL3, a member of NL protein family, are associated with autism. Studies in rodents have found that mutations or deletion of NL3 gene can lead to behavioral disorders in mice, such as social interaction defects, motor hyperactivity and so on. However, the detailed mechanisms are still unclear..Previously, we have found that knockdown of NL3 in cultured rat neurons up-regulated the activation of mTOR signaling, resulting in increased protein synthesis and prolonged dendritic length. The activity of Akt signaling, the upstream of mTOR pathway, was also elevated by NL3 knockdown. Similarly, in vitro cultured cortical neurons from NL3 knockout mice exhibited enlarged soma, prolonged dendritic length, and increased dendritic complexity. Furthermore, we found that the up-regulation of Akt/mTOR signaling associated with NL3 defects was mediated by the reduction in PTEN expression. Based on our Co-IP assays, interaction between NL3 and MAGI2, a PDZ-dependent binding partner of PTEN, was also confirmed, indicating that MAGI2 may be a potential bridge between NL3 and PI3K/PTEN/Akt/mTOR signaling pathway. In summary, our preliminary results suggested that NL3 regulates the development of neurons, especially dendritic development, via modulating Akt/mTOR signaling pathway. .In this study, we will continue to elucidate the detailed mechanism on how NL3 regulates mTOR signaling pathway and find out the proteins whose expression were regulated by the pathway. We will further explore the functional consequence of this NL3-regulated mTOR signaling in neuronal development, synapse formation and neuron transmission, as well as in autism-like behaviors, and examine NL3’s function in different cell types in central nervous system, including glia cells, to clarify the way of NL3-mediated mTOR signaling in leading to autism. Finally, we will try to find new targets in modulating mTOR signaling, use novel as well as traditional inhibitors to down-regulate the mTOR signaling in NL3 knockout mice and evaluate the suitability of these inhibitors as being treatments for autism.