Cdh8-dependent circuit development in autism

自闭症中依赖于 Cdh8 的回路发育

• 批准号: 9895862
• 负责人: Deanna L Benson
• 金额: $ 38.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-06 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895862
• 关键词: Affect; Anatomy; Anxiety; Anxiety Disorders; Attention; Axon; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Biological Assay; Birth; Brain; Cadherins; Cell Adhesion Molecules; Cells; Cognitive; Cognitive deficits; Corpus striatum structure; Couples; Defect; Dendrites; Dendritic Spines; Development; Disease; Dorsal; Electrophysiology (science); Future; Glutamates; Image; Impairment; Impulsivity; Link; Mental disorders; Messenger RNA; Methods; Molecular; Morphology; Mus; Neostriatum; Neurons; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Pathway interactions; Phenotype; Predisposition; Prefrontal Cortex; Rodent; Social Interaction; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Time; Vertebral column; autism spectrum disorder; brain pathway; cadherin 8; cognitive ability; density; experimental study; flexibility; in vivo; information processing; insight; knock-down; mind control; mouse genetics; nervous system disorder; neural circuit; novel; patch clamp; postnatal development; postnatal period; public health relevance; synaptic function; targeted treatment; two photon microscopy

 DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASDs) comprise a range of neurodevelopmental abnormalities in cognitive abilities and behaviors associated with dysfunctional circuitry between the prefrontal cortex (PFC) and the neostriatum. Behavioral abnormalities emerge early after birth and are thought to reflect defects in the finetuning and plasticity of developing functional synaptic connectivity. We have shown that mRNA encoding cadherin8 (Cdh8) - a type II, synaptically localized classic cadherin - is highly enriched in PFC and dorsal striatum during early postnatal development. Moreover, the timing, anatomical distribution, and axon targeting function of Cdh8 suggest strongly that Cdh8 may be crucial for the development and plasticity of PFC→striatal circuitry. This is significant because several recent studies have linked CDH8 genetically to susceptibility to ASDs. Thus, we hypothesize that cognitive ASD like phenotypes reflect impaired synaptic development of PFC→striatal direct and/ or indirect pathway circuitry due to deficient Cdh8 dependent molecular control over these pathways. We will test this hypothesis by combining mouse genetics, anatomy, electrophysiology and behavioral assessment. The vertical integration across these objectives (spanning molecules, synapses, circuits and behaviors) will provide novel insight into molecular control of brain pathways implicated in cognitive and behavioral deficits associated with ASDs. This is important, because corticostriatal circuit defects are central to a number of aberrant behaviors associated with autism and anxiety disorders, but there is surprisingly little known about the normal development and plasticity of such circuits.

 描述(申请人提供)：自闭症谱系障碍(ASD)包括一系列认知能力和行为的神经发育异常，与前额叶皮质(PFC)和新纹状体之间的功能障碍有关。行为异常在出生后很早就出现，被认为反映了发育功能突触连接的微调和可塑性方面的缺陷。我们发现编码钙粘蛋白8(CDH8)的信使核糖核酸(CDH8)--一种突触定位的经典钙粘蛋白--在出生后早期的前额叶核和背侧纹状体中高度丰富。此外，CDH8的时间、解剖分布和轴突靶向功能有力地表明，CDH8可能在→纹状体回路的发育和可塑性中起关键作用。这一点意义重大，因为最近的几项研究已经将CDH8与ASD的易感性联系起来。因此，我们假设认知性房缺的表型反映了纹状体直接和/或间接通路回路的突触发育受损，这是由于依赖→的分子对这些通路的控制不足所致。我们将结合老鼠遗传学、解剖学、电生理学和行为评估来检验这一假说。这些目标(跨越分子、突触、回路和行为)的垂直整合将为分子控制大脑通路提供新的见解，这些通路与自闭症相关的认知和行为缺陷有关。这一点很重要，因为皮质纹状体回路缺陷是自闭症和焦虑症相关的许多异常行为的核心，但令人惊讶的是，人们对这些回路的正常发育和可塑性知之甚少。