自闭症导致儿童社会交往和语言障碍、强迫行为，缺乏有效治疗手段。Shank3在兴奋性突触形成和功能中具有重要作用，该基因缺失是导致自闭症的重要因素。我们前期发现，敲除Shank3基因小鼠出现自闭症样行为，皮质-纹状体谷氨酸能突触功能和结构异常。纹状体由表达多巴胺D1受体的直接通路和D2受体的间接通路组成。两条通路在基底神经节输出控制中相互拮抗，受D1、D2受体调制，其平衡确保基底神经节正确输出，而平衡失调则导致帕金森、成瘾等。自闭症是否与纹状体直接、间接通路失衡有关，尚不清楚。我们发现Shank3敲除小鼠出现间接通路兴奋性突触数目降低，结合环路特征推测自闭症可能由纹状体直接通路强于间接通路失衡导致。本研究将系统研究Shank3敲除小鼠纹状体直接和间接通路兴奋性突触受体功能和多巴胺调控的失衡表现，以期阐明自闭症中纹状体直接、间接通路平衡失调的机制，寻找可能的作用靶点，为自闭症药物治疗提供依据。

Autism spectrum disorders(ASDs) are developmental disorders typically defined by three core symptoms:impaired social relationships, impaired communication and language, repetitive behaviors and restricted interests. Currently, there are no effect pharmacotherapies for managing the core symptoms of the disorder. So developing efficacious treatments for these symptoms is considered to be the primary unmet need in ASDs research. For this to occur, basic research is required to help elucidate the aetiology of ASDs. Recently, Variants of Shank3 have been linked to autism in patients. The Shank family (Shank1-3) gives rise to postsynaptic scaffold proteins implicated in the dendritic spine development and glutamatergic synapse formation. Our previous works found Shank3 knock out (KO) mice exhibit autistic like behaviors. Shank3 is highly expressed in the striata of humans and mice. Our electrophysiological and morphological studies reveal obvious reduction in function and structures of cortical-striatal glutamate synapses. The project neurons of the striatum are medium spiny neurons (MSNs), which can be divided into two major subpopulations: Direct pathway MSNs, which predominantly express D1 dopamine receptors (D1 MSNs), send inhibitory synapses to internal globus pallidus(GPi) and substantia nigra pars reticulata(SNr), whereas indirect pathway MSNs, which predominantly express D2 receptors(D2 MSNs), project mostly to external globus pallidus(GPe) then indirectly excitating GPi/SNr.The balance of two pathways play remarkable role in normal basal ganglion function by dopamine modulation to glutamate synapses. So the imbalance of direct and indirect pathways found be highly related with abnormal behaviors of basal ganglion diseases, such as Parkinson's disease, drugs addiction and Obsessive-Compulsive disorder. Previous works in autism research did not seperate D1 and D2 MSNs pathways, which may be mislead the exact function of direct and indirect pathways balance in autistic like behaviors. Our preliminary electrophysiological data showed reduction of excitatory synapses numbers in D2 MSNs but not D1 MSNs, which provide the evidence of imbalance between direct and indirect pathways causing autisms like behavior in Shank3 KO mice. We are planning do further works to research excitatory synaptic function and dopamine modulation of cortical-striatal pathways by seperating D1 and D2 MSNs in Shank3 KO mice with bacterial artificial chromosome trangenic technology. Then we can find a way to rescue autistic like behavior by rebalancing D1 and D2 MSNs activities in vivo. From that, we can demonstrate clear role of direct and indirect pathways balance in ASDs and help to find the target for pharmacotherapies of the core symptoms of ASDs.