Synaptic pathophysiology of the 16p11.2 microdeletion mouse model

 描述(由申请人提供)：目前还没有基于机制的疗法可用于自闭症谱系障碍(ASD)和智力残疾(ID)。主要的障碍一直是识别大脑中扰乱行为和认知的缺陷细胞过程。越来越多的证据表明，许多ASD和ID病例都有遗传病因。然而，这些基因变化很多，往往非常罕见，而且非常多样化。理解这些发现的一种方法是假设过多的基因突变可能类似地扰乱一组常见的生理过程，这些过程最终在行为上表现为ID和ASD。验证这一假设至关重要，因为它不仅缩小了对疾病发病机制的研究范围，而且还提出了可能广泛适用于整个病因学类别的治疗策略。与ID和ASD相关的单基因疾病动物模型的研究支持了这样的观点，即病理生理学的一个轴是代谢性谷氨酸受体5(MGluR5)介导的突触蛋白合成和可塑性。在脆性X综合征(FX)动物模型中，mGluR5介导的海马区蛋白质合成和可塑性被夸大。相反，在结节性硬化症(TSC)的动物模型中，mGluR5下游的蛋白质合成和可塑性减弱。特别有趣的是，抑制mGluR5纠正了FX模型中的认知(和许多其他)缺陷，而正向调制mGluR5纠正了TSC模型中的认知缺陷。在目前的工作中，我们正在询问人类染色体16p11.2的基因拷贝数变异是否类似地扰乱了这一核心突触机制。人类染色体16p11.2是精神疾病的一种多基因原因，可能包括ID和ASD。受影响区域的许多基因被预测参与蛋白质合成调节的发现，以及16p11.2微缺失小鼠模型的初步数据显示，mGluR5介导的突触可塑性和认知功能中断，并通过长期抑制mGluR5纠正记忆缺陷，从而提出了这一假说。我们建议的研究的具体目的是：(A)进一步表征16p11.2 CNV模型小鼠海马区突触传递和可塑性的状态；(B)表征这些小鼠的突触蛋白合成和可能被破坏的分子信号通路；(C)进一步评估16p11.2 CNV模型小鼠的行为缺陷；以及(D)尝试通过先前在FX和TSC动物模型中验证的合理药物治疗来纠正记忆障碍。

 DESCRIPTION (provided by applicant): Currently there are no mechanism-based therapies available for autism spectrum disorders (ASDs) and intellectual disability (ID). The main barrier has been identifying the defective cellular processes within the brain that disrupt behavior and cognition. Increasing evidence indicates that many cases of ASD and ID have a genetic etiology. However, these genetic changes are numerous, often very rare, and remarkably diverse. One way to make sense of these findings is to assume that a plethora of gene mutations may similarly disrupt a common set of physiological processes that ultimately manifest behaviorally as ID and ASD. Testing this assumption is of paramount importance, as not only does it narrow the search for mechanisms of disease pathogenesis, but it also suggests therapeutic strategies that might apply broadly to an entire class of etiologies. Work on animal models of single-gene disorders associated with ID and ASD has supported the idea that one axis of pathophysiology is metabotropic glutamate receptor 5 (mGluR5) mediated synaptic protein synthesis and plasticity. In the animal model of fragile X syndrome (FX), mGluR5-mediated protein synthesis and plasticity in the hippocampus are exaggerated. Conversely, in the animal model of tuberous sclerosis complex (TSC), protein synthesis and plasticity downstream of mGluR5 are diminished. Of particular interest, inhibition of mGluR5 corrects cognitive (and many other) deficits in the FX model, whereas positive modulation of mGluR5 corrects cognitive defects in the TSC model. In the current work, we are asking if gene copy number variation at human chromosome 16p11.2, a polygenic cause of psychiatric illness that can include ID and ASD, similarly disrupts this core synaptic mechanism. This hypothesis is suggested by the findings that many genes in the affected region are predicted to be involved in protein synthesis regulation, and preliminary data in the mouse model of 16p11.2 microdeletion showing disrupted mGluR5-mediated synaptic plasticity and cognitive function, and correction of memory deficits by chronic inhibition of mGluR5. The specific aims of our proposed research are to (a) further characterize the state of synaptic transmission and plasticity in the hippocampus of 16p11.2 CNV model mice, (b) characterize synaptic protein synthesis and the molecular signaling pathways which may be disrupted in these mice, (c) further assess the behavioral deficits in 16p11.2 CNV model mice, and (d) attempt to correct memory deficits with rational pharmacotherapies previously validated in animal models of FX and TSC.