孤独症是一种严重的神经发育障碍性疾病，其发病机制尚不明确。近来的研究表明，突触发育和髓鞘化异常是孤独症发病的重要因素。微管结合蛋白是神经细胞骨架的关键成分，参与轴突导向及突触发育。项目组前期的研究发现，微管结合蛋白STOP在孤独症患者外周血和动物模型BTBR小鼠大脑皮层显著低表达；BTBR小鼠兴奋性递质谷氨酸的释放及髓鞘相关蛋白的表达明显减少，但两者间的作用机制仍不清楚。本项目拟利用BTBR小鼠作为研究对象，通过增强脑内STOP蛋白的表达，考察其对小鼠孤独症相关行为学的效应，进一步证实其在孤独症发病中的作用；运用磁共振波谱和扩散张量成像技术从整体层面，采用形态学、免疫学和电生理学等方法从细胞分子层面，体内和体外研究STOP蛋白对神经元兴奋性突触结构和传递功能以及少突胶质细胞髓鞘化的影响，探讨微管结合蛋白STOP参与孤独症发病的作用机制，以期为治疗孤独症提供新的理论基础和实验依据。

Autism is a highly disabling neurodevelopmental disorder, however the pathogenesis of the disorder is still unknown. Increasing evidence suggests that abnormalities in synaptic function and myelination may contribute to phenotypic deficits. The microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton and participate in determining axon guidance and synaptic plasticity in nervous sysytem. Previous research showed that stable tubule only polypeptide (STOP, also known as MAP6) protein was significantly reduced in the plasma of autistic subjects and the brain from BTBR mice, a mouse model that displays an autism-like phenotype. Further, the evoked glutamate release and the levels of myelin-related proteins in the cerebral cortex of BTBR mice were significantly lower than that in B6 mice with high level sociability. The mechanism underlying STOP protein involved in the mediation of autism-like behaviors through regulating synaptic function and myelination is poorly understood. In this project, using the BTBR mouse model of autism, the STOP protein will be locally elevated by intracerebroventricular injection of STOP lentivirus. The behavioral tests including social behaviors, ultrasonic vocalizations and repetitive behaviors will be carried out to analyze whether the autism-like behaviors are modulated. The magnetic resonance spectroscopy, diffusion tensor imaging, immunofluorescence and electrophysiological techniques will be employed to explore the effects of STOP protein in the structure and function of excitatory synapse in neurons and myelination in oligodendrocytes in vivo and in vitro. The goal of this study is to investigate the possible mechanism of microtubule-associated protein STOP in the pathogenesis of autism.