孤独谱系障碍（Autism spectrum disorder，ASD）作为儿童神经发育性疾病，其沟通交流障碍症状广为关注，而刻板行为相对忽视。刻板行为是ASD病人最早症状，常加重患者交流障碍和家人的负担，神经基础尚不清楚。我们以往发现，Shank3缺失导致纹状体兴奋性突触异常可能参与ASD行为。我们新近证实，Shank3敲除导致小鼠纹状体间接通路兴奋性突触受损，直接通路相对正常。化学遗传学提高间接通路活动可改善刻板行为。然而，纹状体接收皮质、丘脑双重谷氨酸能支配，两条通路突触结构功能存在区别，是否在刻板行为中作用不同，尚不清楚。本研究拟在前期基础上，利用病毒标记技术、光遗传技术、荧光小鼠和Cre小鼠等工具鼠，选择性记录或调控皮质-纹状体通路和丘脑-纹状体通路谷氨酸突触，系统研究两条通路谷氨酸能突触功能结构改变及在ASD刻板行为中可能作用，探讨刻板行为的病理生理机制，寻找可能的诊疗策略。

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which present two types of symptoms: deficits in social communication / interaction and restricted / repetitive behaviors. Comparing to social communication/interaction deficits, repetitive behaviors often get overlooked. However, repetitive behaviors usually are the first sign of ASD patients and can keep in a lifetime. It also aggravate the social communication/interaction deficits of ASD patients and also the anxiety and burden of whole family. Recent genetic studies have revealed that some genes coding proteins important for synaptic development and function may be involved in ASD. Shank3 (SH3 and multiple ankyrin repeat domains 3) is a member of the Shank family of proteins (SHANK1-3) which interact with various postsynaptic density (PSD) proteins. It shows an important role in dynamically regulating excitatory synaptic development, function and structure. Genetic studies have strongly implicated that SHANK3 gene disruption or mutation may be a monogenic cause of ASD. Our previous work found Shank3 mutant mice exhibited ASD-like behavioral including repetitive grooming behaviors and social interaction deficits. Thus, the excitatory synapse deficit produced by Shank3 mutant may be particpated in neural mechanisms underlying ASD relevant behaviors. Recently we demonstrated that Shank3 deletion preferentially affected synapses onto striatal indirect pathway projection medium spiny neurons (Striatopallidal MSNs). Striatopallidal MSNs showed severe defects including synaptic transmission, synaptic plasticity and spine density. Importantly, the repetitive grooming behavior was rescued by selectively enhancing the striatopallidal MSNs activity using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs-hM3Dq) technology. However, the striatum receives two excitatory synapses from cortex and thalamus. The excitatory synapses of cortico-striatal pathway (CSP) and thalamo-striatal pathway (TSP) show different synaptic location and transimission properties. It is not clear whether the glutamatergic synapse of CSP and TSP are differentially affected in Shank3 mutant mice. We are planning do serial works to research excitatory synaptic function and structure of CSP and TSP by specific targeting or modulateing CSP/TSP synpase on D1 and D2 MSNs in Shank3 KO mice with virus labeling, optogenetics, transgenic mice such as D1-Tdtomato, D2-GFP, D1-Cre and D2-Cre mice. We are also planning to test the relationship between CSP/TSP and repetitive behavior. We hope we can find a working flow of CSP and TSP modulating repetitive behavior and help to find the target for the diagnosis and therapies of repetitive behavior of ASDs.