Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice

Shank3B-/-小鼠早期皮质纹状体功能障碍的机制及致病作用

• 批准号: 10515329
• 负责人: Rui Peixoto
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515329
• 关键词: Acceleration; Address; Adult; Affect; Animals; Behavior; Behavioral; Biological Models; Brain; Cells; Cognitive deficits; Corpus striatum structure; Cre driver; Cyclic AMP-Dependent Protein Kinases; Defect; Development; Disease; Environment; Exhibits; Functional disorder; Genetic; Genetic study; Glutamates; Growth; Hyperactivity; Hypertrophy; Impairment; Intervention; Knowledge; Label; Laboratories; Light; Molecular; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Peptides; Phase; Phenotype; Population; Prefrontal Cortex; Process; Protein Inhibition; Protein Kinase A Inhibitor; Reporter Genes; Reporting; Risk; Role; Social Interaction; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Viral; Wild Type Mouse; Work; autism spectrum disorder; autistic; cohort; imaging study; individuals with autism spectrum disorder; insight; loss of function; maladaptive behavior; motor deficit; nerve supply; neural; neuropathology; optogenetics; postnatal; postnatal development; postnatal period; protein expression; repetitive behavior; response; risk variant; social deficits; synaptogenesis; targeted treatment

PROJECT SUMMARY Despite increasing knowledge of the genetic underpinnings of autism risk, the specific pathogenic mechanisms underlying the emergence of motor and cognitive deficits in autism spectrum disorders (ASD) remain unclear. Recent imaging and genetic studies have pointed to corticostriatal dysfunction has a prevalent pathophysiology in ASD. In particular, hypertrophy and abnormal functional connectivity of prefrontal cortex (PFC) and dorsomedial striatum (DMS) have been reported in multiple autistic individuals, providing a potential neuropathological substrate for the repetitive behaviors and social deficits associated with autism. Our laboratory has shown that mice with loss of function deletions in SHANK3 (Shank3B-/-), a highly penetrant monogenic cause of autism, exhibit hyperactivity and abnormal patterns of connectivity in corticostriatal circuits during postnatal development. Behavioral deficits in these animals also emerge during these early developmental periods, suggesting that early corticostriatal dysfunction might be an important pathogenic mechanism in SHANK3 associated disorders. Here we propose to further characterize how striatal circuit development is impaired by loss of Shank3 and identify the specific corticostriatal pathways affected in these conditions (Aim1). In addition, using recently developed conditional transgenic mice that allow cell-specific manipulation of Shank3 expression we will dissect the specific mechanisms leading to corticostriatal connectivity abnormalities (Aim 2). In addition, using new molecular strategies that normalize early excitatory drive in striatal neurons, we will determine the pathogenic role of early striatal circuit dysfunction in the emergence of maladaptive behaviors in Shank3B-/- mice (Aim 3). This work will advance our understanding of the basic mechanisms and developmental rules regulating the maturation of corticostriatal circuits and provide important insights into the pathogenesis of ASD and other neurodevelopmental disorders with early activity imbalances in corticostriatal circuits.

项目摘要 尽管越来越多的知识的遗传基础的自闭症风险，具体的致病机制， 自闭症谱系障碍（ASD）中运动和认知缺陷的出现的潜在原因尚不清楚。 最近的成像和遗传学研究指出，皮质纹状体功能障碍具有普遍的病理生理学 在ASD特别是，前额叶皮层（PFC）的肥大和异常功能连接， 背内侧纹状体（DMS）已报告在多个自闭症患者，提供了一个潜在的 孤独症是与孤独症相关的重复行为和社会缺陷的神经病理学基础。我们 实验室已经表明，具有SHANK 3（Shank 3B-/-）功能缺失的小鼠， 自闭症的单基因原因，表现出过度活跃和皮质纹状体回路连接模式异常 在出生后的发育过程中。这些动物的行为缺陷也出现在这些早期 发育期，表明早期皮质纹状体功能障碍可能是一个重要的致病 SHANK 3相关疾病的机制。在这里，我们建议进一步描述纹状体回路 Shank 3的缺失损害了发育，并确定了在这些过程中受影响的特定皮质纹状体通路。 条件（Aim 1）。此外，使用最近开发的条件转基因小鼠，允许细胞特异性 操纵Shank 3的表达，我们将剖析导致皮质纹状体的具体机制， 连接异常（目标2）。此外，使用新的分子策略，使早期兴奋性 我们将确定早期纹状体回路功能障碍在纹状体神经元中的致病作用， 在Shank 3B-/-小鼠中出现适应不良行为（目的3）。这项工作将促进我们对 为进一步阐明皮质纹状体神经回路成熟的基本机制和发育规律提供理论依据 对ASD和其他具有早期活动的神经发育障碍的发病机制的重要见解 皮质纹状体回路失衡