The Striatal Circuitry Underlying Autistic-Like Behaviors

自闭症样行为背后的纹状体回路

• 批准号: 8550541
• 负责人: Michael Frederick Wells
• 金额: $ 3.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550541
• 关键词: 22q13.3; Ablation; Affect; Animal Model; Autistic Disorder; Behavior; Behavioral; Biochemical; Brain; Candidate Disease Gene; Centers for Disease Control and Prevention (U.S.); Child; Cognitive; Corpus striatum structure; Data; Defect; Disease; Equilibrium; Etiology; Excision; Functional disorder; Future; Genes; Goals; Grooming; Habits; Hippocampus (Brain); Human; Human Genetics; Image; Investigation; Knockout Mice; Laboratories; Language Development; Lead; Link; Messenger RNA; Motor; Motor Cortex; Motor output; Movement; Mus; Mutant Strains Mice; Neurodevelopmental Disorder; Neurons; Output; Pathway interactions; Patients; Play; Protein Family; Proteins; Role; Scaffolding Protein; Signal Transduction; Social Interaction; Stereotyped Behavior; Structure; Symptoms; Synapses; Synaptic Transmission; Syndrome; Techniques; Testing; Therapeutic Intervention; Time; association cortex; autism spectrum disorder; base; density; expectation; meetings; member; mouse genome; mutant mouse model; neural circuit; neuronal circuitry; novel; reward processing; social

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.

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，影响大约 110 名儿童中的 1 名（CDC，2009）。自闭症谱系障碍的特征是存在三种主要症状：社交互动缺陷、重复或刻板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自闭症谱系障碍（ASD）候选基因，但与这些疾病病因学相关的一般机制和大脑回路在很大程度上仍未被破译。 特别是对一种基因的研究可能有助于理解 ASD 背后难以捉摸的疾病机制。 Shank3 是突触后密度的支架蛋白，是 Shank 蛋白家族中唯一在纹状体中富集的成员。由于大量研究将 Shank3 的破坏与受影响的人类患者联系起来，该基因已成为 ASD 的一个有吸引力的候选基因。最近，我们的实验室生成并表征了一种新型 Shank3B 突变小鼠，发现其存在社交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种纹状体神经元畸变。 该项目的长期目标是了解 Shank3B 突变小鼠 ASD 样行为背后的神经回路，以确定治疗干预的潜在目标。我假设有缺陷的纹状体电路在 这些异常行为。为了直接检验这个假设，我将生成一只 Shank3B 条件敲除小鼠。然后，我将使用这只小鼠从纹状体中专门去除 Shank3，期望这种区域特异性消融将重现 Shank3B 突变小鼠中发现的重复行为和社交互动缺陷。为了进一步探讨纹状体回路缺陷对这些行为的影响，我将生成直接和间接通路特异性 Shank3 敲除小鼠品系，并分析它们的社交互动和刻板行为。如果成功，这些研究可以为纹状体功能障碍作为自闭症动物模型中重复行为和异常社交互动行为的机制提供第一个直接证据。