Cdh8-dependent circuit development in autism

 描述（由申请人提供）：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，与前额叶皮层（PFC）和新纹状体之间的功能障碍性回路相关。行为异常在出生后早期出现，被认为反映了发育中功能性突触连接的微调和可塑性缺陷。我们已经表明，mRNA编码钙粘蛋白8（Cdh 8）-II型，突触本地化的经典钙粘蛋白-是高度富集在PFC和背侧纹状体在出生后早期的发展。此外，Cdh 8的时间，解剖分布和轴突靶向功能强烈表明Cdh 8可能对PFC→纹状体回路的发育和可塑性至关重要。这是重要的，因为最近的几项研究将CDH 8与ASD的易感性遗传联系起来。因此，我们假设认知ASD样表型反映了PFC→纹状体直接和/或间接通路回路的突触发育受损，这是由于对这些通路的Cdh 8依赖性分子控制不足所致。我们将结合小鼠遗传学、解剖学、电生理学和行为评估来验证这一假设。这些目标（跨越分子，突触，电路和行为）的垂直整合将提供新的见解，涉及与ASD相关的认知和行为缺陷的大脑通路的分子控制。这一点很重要，因为皮质纹状体回路缺陷是与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。

 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.