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

描述(由申请人提供)：几种表现为自闭症和智力残疾的基因定义的发育障碍，如脆性X染色体(FX)和结节性硬化症(TSC)，都有共同的突触活动调节蛋白质合成中断。了解神经活动是如何调节突触蛋白合成的，对于确定这些疾病的新治疗方法至关重要。一个关键的机制是利用代谢性谷氨酸受体5(MGluR5)，但该受体如何耦合到mRNA翻译机制仍有待确定。在这里，我们检验了这样的假设，即mGluR5和蛋白质合成之间的关键联系是由β-arrestin提供的。我们的具体目的是研究β-arrestin基因减少对(1)mGluR5信号和海马区蛋白质合成的影响，(2)使用电生理学方法研究海马区突触功能和蛋白质合成依赖的可塑性，以及(3)Fmr1基因敲除小鼠表达的脆性X行为和电生理表型的影响。如果我们的假设是正确的，我们希望通过减少β-arrestin来观察脆性X表型的改善，验证mGluR5-β-arrestin蛋白复合体作为新的治疗靶点。

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 β-arrestin. Our specific aims are to characterize the effect of β-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 β-arrestin, validating the mGluR5-β-arrestin protein complex as a novel therapeutic target.