The Striatal Circuitry Underlying Autistic-Like Behaviors

描述(由申请人提供)：自闭症谱系障碍(ASD)包括一组神经发育障碍，大约每110名儿童中就有一人受到影响(CDC，2009年)。自闭症的特征是存在三个主要症状：社交障碍、重复或刻板印象的行为以及语言发育异常。尽管最近的人类遗传学研究已经确定了几个ASD候选基因，但这些疾病的病因学中涉及的一般机制和大脑回路在很大程度上仍未破译。尤其是对一个基因的研究可能有助于理解自闭症背后难以捉摸的疾病机制。SHANK3是一种突触后密度的支架蛋白，是唯一在纹状体中丰富的Shank蛋白家族成员。由于大量研究将Shank3基因的中断与受影响的人类患者联系起来，该基因已成为ASDS的一个有吸引力的候选基因。最近，我们实验室培育了一只新的Shank3B突变小鼠，并对其进行了鉴定，发现其存在社会互动缺陷和重复行为。对这些异常原因的进一步研究发现了皮质-纹状体突触传递的缺陷以及其他几个纹状体神经元的异常。该项目的长期目标是了解Shank3B突变小鼠ASD样行为背后的神经电路，以便确定潜在的治疗干预靶点。我推测纹状体环路的缺陷在 这些不正常的行为。为了直接测试这一假设，我将生成一个Shank3B条件基因敲除小鼠。然后，我将使用这只小鼠从纹状体中专门移除Shank3，期望这种特定区域的消融将概括在Shank3B突变小鼠中发现的重复行为和社会互动缺陷。为了进一步探讨纹状体回路缺陷对这些行为的影响，我将建立直接和间接途径特异性的Shank3基因敲除小鼠系，并分析它们的社会互动和刻板行为。如果成功，这些研究可能提供第一个直接证据，证明纹状体功能障碍是自闭症动物模型中重复行为和异常社交行为的机制。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) comprise a group of neurodevelopmental disorders that affect approximately 1 in 110 children (CDC, 2009). ASDs are characterized by the presence of three cardinal symptoms: social interaction deficits, repetitive or stereotyped behaviors, and abnormal language development. Though recent human genetics studies have identified several ASD candidate genes, the general mechanisms and brain circuitry involved in the etiology of these disorders remain largely undeciphered. The study of one gene in particular may be helpful in understanding the elusive disease mechanisms underlying ASDs. Shank3 is a scaffolding protein of the post-synaptic density that is the only member of the Shank family of proteins to be enriched in the striatum. Due to the multitude of studies connecting disruptions of Shank3 to affected human patients, this gene has become an attractive candidate gene for ASDs. Recently, our laboratory generated and characterized a novel Shank3B mutant mouse and discovered the presence of social interaction deficits and repetitive behaviors. Further investigation into the cause of these abnormalities identified defects in cortico-striatal synaptic transmission as well as several other striatal neuron aberrations. The long-term goal of this project is to understand the neural circuitry underlying the ASD-like behaviors in Shank3B mutant mice in order to identify potential targets for therapeutic intervention. I hypothesize that defective striatal circuitry plays a causative role in these abnormal behaviors. To directly test this hypothesis, I will generate a Shank3B conditional knockout mouse. I will then use this mouse to remove Shank3 exclusively from the striatum with the expectation that this region-specific ablation will recapitulate the repetitive behaviors and social interaction deficits found in the Shank3B mutant mice. To further probe the influence of defective striatal circuitry on these behaviors, I will then generate direct- and indirect pathway-specific Shank3 knockout mouse lines and analyze their social interactions and stereotyped behaviors. If successful, these studies could provide the first direct evidence for striatal dysfunction as a mechanism for repetitive behaviors and abnormal social interaction behaviors in an animal model of autism.