兴奋性突触发育异常导致ASD社交障碍的机制研究

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders starting at babies and toddlers and keeping whole life. Defect in social communication and social interaction is one of the core symptoms of ASD. Because of unclear mechanisms, there still have no efficient treatment on ASD. Several studies have suggested that the abnormality of synaptic development is related to the pathogenesis of ASD. ASD related high risk gene Shank3 (SH3 and multiple ankyrin repeat domains 3) could directly modulate the development of synapse and finally affect the structure and function of synapses. Shank3 deficiency resulted in excitatory synaptic defect and may be one of critical mechanisms in ASD. Our recently research found that the social communication/social interaction deficit of Shank3 KO mice were highly related with the structure and function abnormality of excitatory synapses in anterior cingulate cortex (ACC). The impaired excitatory synapse occurred during the early postnatal periods of Shank3 KO mice. These results suggested that the developmental abnormality of excitatory synapse in ACC may be one of key mechanisms for the core symptoms of ASD. However, it is still unclear about the characteristics and mechanisms of excitatory synaptic developmental abnormality of ACC in Shank3 KO mice, and what’s the exact role of the abnormality of excitatory synaptic development in social communication/social interaction deficit. So in the present study, we will use Shank3 KO mice as ASD model, combining with multiple techniques including neurodevelopment, electrophysiology and optogenetics, to observe the detailed developmental changes in excitatory synapses and synaptic homeostasis induced by Shank3 deficiency, reveal the molecular mechanisms of excitatory synaptic development, and explore the relationship between the improvement of social communication/social interaction and the recovery of excitatory synapses at developmental stage of Shank3 KO mice. The finding of our study will be helpful for understanding the mechanism of the core symptoms in ASD and provide a new thought for the early diagnosis and treatment of ASD.

自闭症谱系障碍（ASD）是神经发育障碍性疾病，患儿出现社交障碍等核心症状，因机制不清，故治疗手段缺乏。研究发现ASD与突触发育异常有关，而ASD敏感基因Shank3缺失可致兴奋性突触功能异常，参与ASD发病。我们发现Shank3 KO小鼠社交障碍与前扣带回皮质（ACC）兴奋性突触功能异常相关，而且兴奋性突触受损始于生后发育阶段，提示ACC兴奋性突触发育异常可能是ASD核心症状的发生原因，但ACC兴奋性突触发育异常的特征与机制、其在社交障碍发生中的作用等仍需深入研究。我们将利用Shank3 KO小鼠，综合应用神经发育、电生理、光遗传等多种技术，系统研究Shank3缺失致ACC神经元兴奋性突触结构功能发育和突触稳态变化特征，探讨ACC兴奋性突触发育异常的分子机制，验证发育阶段ACC兴奋性突触修复对ASD社交障碍的改善效应。本课题将揭示ASD核心症状发生的关键机制，为ASD早期诊疗提供新思路。

孤独症谱系障碍（ASD）是一组起始于婴幼儿时期的神经发育障碍性疾病，其中社交行为障碍是ASD核心症状之一，目前缺少有效的干预手段，主要原因在于其发病机制不明。本项目从兴奋性突触发育切入，利用Shank3基因敲除和VPA孕期诱导两种ASD小鼠模型，综合应用神经发育、电生理、光遗传以及分子生物学等多种技术，对ASD兴奋性突触发育异常参与社交障碍发生机制进行系统探究。相关研究发现如下：第一，阐明了Shank3基因缺失ASD小鼠模型中ACC兴奋性突触结构及功能发育异常的变化规律，发现生后两周是ASD兴奋性突触发育异常的关键时间点；第二，发现ASD小鼠模型ACC突触稳态存在异常，并讨论了不同类型抑制性突触对社交行为的影响；第三，观察了发育期调控Shank3基因对ACC兴奋性突触结构功能及社交行为的影响，通过调控Shank3基因在发育阶段重新表达，发现能够改善兴奋性突触结构及功能损伤，并改善ASD小鼠的社交行为异常；第四，对ASD动物模型ACC突触发育异常的分子机制进行了探索，发现了Wnt/β-catenin信号介导的糖酵解异常诱发了兴奋性突触发育受损、局部BDNF水平异常导致了ACC突触稳态失衡；第五，我们开发了发育期靶向调控ACC内关键信号分子的干预策略，利用XAV939药理学干预能够改善ASD突触损伤及社交障碍，另外局部给与BDNF能够改善ACC突触稳态及社交异常；最后，本项目在相关发现的基础上，从ASD患者影像学、精准干预等角度进行了方法学的初步探究，为未来临床的早期诊断和干预提供研究基础。本项目的相关发现揭示了兴奋性突触发育异常参与ASD社交行为障碍的机制，为ASD社交障碍的发育异常机制提供了实验证据，为ASD早期诊断及治疗提供科学依据。

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