The Striatal Circuitry Underlying Autistic-Like Behaviors

自闭症样行为背后的纹状体回路

• 批准号: 8399238
• 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/8399238
• 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. PUBLIC HEALTH RELEVANCE: Recent studies have proposed disruption of the Shank3 gene to be the causative agent in several cases of human autism spectrum disorders (ASDs), specifically the 22q13.3 deletion syndrome. At the same time, behavioral analysis of the Shank3B mutant mouse revealed ASD-like behaviors, including social interaction deficits and compulsive grooming. This project will set out to understand the neuronal circuitry underlying the behavioral defects in the Shank3B mutant mouse, with the intended goal of identifying targets for future therapeutic interventions.

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，约影响1/110的儿童（CDC，2009）。ASD的特征在于存在三个主要症状：社会互动缺陷，重复或刻板行为，以及异常的语言发育。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所涉及的一般机制和脑回路仍然在很大程度上未被破译。 特别是对一个基因的研究可能有助于理解ASD背后难以捉摸的疾病机制。Shank 3是突触后密度的支架蛋白，其是在纹状体中富集的Shank蛋白家族的唯一成员。由于大量研究将Shank 3的破坏与受影响的人类患者联系起来，该基因已成为ASD的有吸引力的候选基因。最近，我们的实验室产生并表征了一种新的Shank 3B突变小鼠，并发现了社会互动缺陷和重复行为的存在。对这些异常原因的进一步研究发现皮质-纹状体突触传递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Shank 3B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靶点。我推测纹状体回路的缺陷在 这些不正常的行为。为了直接测试这个假设，我将产生Shank 3B条件性敲除小鼠。然后，我将使用这只小鼠专门从纹状体中去除Shank 3，期望这种区域特异性消融将重现Shank 3B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，我将产生直接和间接途径特异性Shank 3基因敲除小鼠品系，并分析它们的社会互动和刻板行为。如果成功，这些研究可以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会互动行为的机制。 公共卫生关系：最近的研究提出Shank 3基因的破坏是人类自闭症谱系障碍（ASD），特别是22q13.3缺失综合征的几个病例的致病因素。与此同时，对Shank 3B突变小鼠的行为分析揭示了类似ASD的行为，包括社会互动缺陷和强迫性梳理。该项目将着手了解Shank 3B突变小鼠行为缺陷背后的神经元回路，其预期目标是确定未来治疗干预的目标。