Cdh8-dependent circuit development in autism

自闭症中依赖于 Cdh8 的回路发育

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：自闭症谱系障碍 (ASD) 包括一系列与前额皮质 (PFC) 和新纹状体之间的功能失调回路相关的认知能力和行为神经发育异常。行为异常在出生后早期出现，被认为反映了这些异常。发育中的功能性突触连接的微调和可塑性缺陷局部经典钙粘蛋白 - 在出生后早期发育过程中在 PFC 和背侧纹状体中高度富集。此外，Cdh8 的时间、解剖分布和轴突靶向功能表明 Cdh8 可能对于 PFC→纹状体回路的发育和可塑性至关重要。意义重大，因为最近的几项研究已将 CDH8 与 ASD 易感性联系起来，因此，我们认为认知 ASD 样表型反映了 ASD 的突触发育受损。 PFC→纹状体直接和/或间接通路电路，由于 Cdh8 依赖的分子控制这些通路的缺陷，我们将通过结合小鼠遗传学、解剖学、电生理学和行为评估来测试这一假设。神经回路和行为）将为与 ASD 相关的认知和行为缺陷相关的大脑通路的分子控制提供新的见解，这很重要，因为皮质纹状体回路缺陷是许多相关异常行为的核心。与自闭症和焦虑症有关，但令人惊讶的是，人们对这种回路的正常发育和可塑性知之甚少。