Validating a novel target for correction of pathophysiology in fragile X and TSC

描述（由申请人提供）：表现为自闭症和智力残疾的几种遗传定义的发育障碍，如脆性X（FX）和结节性硬化症（TSC），共同具有突触活性调节蛋白质合成的破坏。了解神经活动如何调节突触蛋白合成对于确定这些疾病的新治疗方法至关重要。一个关键的机制采用代谢型谷氨酸受体5（mGluR 5），但它仍然是建立如何受体耦合到mRNA翻译机制。在这里，我们测试的假设，mGluR 5和蛋白质合成之间的一个关键环节是由β-arrestin提供。我们的具体目标是表征ss-arrestin基因减少对（1）使用生物化学方法的海马中mGluR 5信号传导和蛋白质合成的影响，（2）使用电生理方法的海马突触功能和蛋白质合成依赖性可塑性，以及（3）在Fmr 1敲除小鼠中表达的脆性X行为和电生理表型。如果我们的假设是正确的，我们期望通过减少β-抑制蛋白来观察脆性X表型的改善，从而验证mGluR 5-β-抑制蛋白蛋白复合物作为新的治疗靶标。

DESCRIPTION (provided by applicant): Several genetically defined developmental disorders that manifest as autism and intellectual disability, such as fragile X (FX) and tuberous sclerosis complex (TSC), have in common a disruption of activity-regulated protein synthesis at synapses. Understanding how neural activity regulates synaptic protein synthesis is crucial for identifying new therapuetic approaches for these diseases. One key mechanism employs metabotropic glutamate receptor 5 (mGluR5) but it remains to be established how this receptor couples to the mRNA translation machinery. Here we test the hypothesis that a crucial link between mGluR5 and protein synthesis is provided by ß-arrestin. Our specific aims are to characterize the effect of ss-arrestin genetic reduction on (1) mGluR5 signaling and protein synthesis in the hippocampus using biochemical methods, (2) hippocampal synaptic function and protein synthesis-dependent plasticity using electrophysiological methods, and (3) on fragile X behavioral and electrophysiological phenotypes expressed in the Fmr1 knockout mouse. If our hypothesis is correct, we expect to observe an amelioration of fragile X phenotypes by reducing ß-arrestin, validating the mGluR5-ß-arrestin protein complex as a novel therapeutic target.