Pathophysiology and treatment of fragile X and related disorders

目前还没有机制为基础的治疗自闭症谱系障碍 （ASD）和智力残疾（ID）。两个主要障碍是识别缺陷 大脑中破坏行为和认知的细胞过程，以及对一个 基于病理生理学的客观生物标志物，可用于患者分层， 评估治疗反应。本项目的目标是解决这些缺陷 使用脆性X综合征的小鼠模型，脆性X综合征是人类ID和ASD的主要原因。脆性X 是由X染色体上FMR 1基因的沉默和编码蛋白的丢失引起的 FMRP。FMRP缺失的主要后果包括蛋白质的调节被破坏， 神经元合成、离子通道功能改变以及抑制回路发育改变 在大脑皮层中。先前在Fmr1 KO小鼠中的研究表明， 基础蛋白质合成中的急剧正确的改变也改善了多种结构， 生化和行为缺陷因此，一个有希望的研究方向需要了解 蛋白质合成的操作如何恢复正常的神经元功能。我们的研究在 Fmr1基因敲除小鼠的视觉皮层（V1）显示，层（L）5 V1神经元的过度兴奋性 是通过抑制异常蛋白质合成来纠正的细胞自主表型。 这种表型可能与人类高度破坏性的感觉高反应性有关 脆性X和其他形式的ASD，但无论如何，它是一个有用的报告功能 改变蛋白质合成的结果。值得注意的是，这种表型的逆转 快速地，在60分钟内抑制蛋白质合成。这些数据表明 具有短半衰期的蛋白质，通过抑制mRNA翻译而迅速耗尽。目标1， 在这个探索性的项目中，我们将利用基因获取L5亚群的优势， 神经元来识别这些蛋白质。如果成功，这种方法将产生一个新的清单， 与脆性X染色体异常蛋白质合成相关的治疗靶点。在目标2中，我们 评估我们在L5中发现的一般性，并调查这种特定致病性的影响。 对清醒小鼠V1功能的影响。这些实验将产生新的功能 体内治疗效果的测量，如果转化为人类，可以用作潜在的 脆性X染色体及相关疾病中一类特定病理生理机制的生物标志物 紊乱

Currently there are no mechanism-based therapies available for autism spectrum disorders (ASDs) and intellectual disability (ID). Two major barriers are the identification of defective cellular processes within the brain that disrupt behavior and cognition, and the validation of an objective biomarker based on pathophysiology that can be used for patient stratification and assessing treatment response. The objectives of this project are to address these deficiencies using the mouse model of fragile X syndrome, a leading cause of human ID and ASD. Fragile X is caused by silencing of the FMR1 gene on the X chromosome and loss of the encoded protein FMRP. Major consequences of the loss of FMRP include disrupted regulation of protein synthesis in neurons, altered ion channel function, and altered development of inhibitory circuits in the cerebral cortex. Previous studies in the Fmr1 KO mouse showed that manipulations that acutely correct alterations in basal protein synthesis also improve a wide variety of structural, biochemical, and behavioral deficits. Thus, one promising line of research entails understanding how the manipulations of protein synthesis restore normal neuronal function. Our studies in the visual cortex (V1) of Fmr1 KO mice have shown that hyperexcitability of layer (L) 5 V1 neurons is a cell-autonomous phenotype that is corrected by suppressing aberrant protein synthesis. This phenotype may be relevant to sensory hyperresponsivity that is highly disruptive in human fragile X and other forms of ASD, but regardless it is a useful reporter of a functional consequence of altered protein synthesis. Remarkably, reversal of this phenotype occurs rapidly, within 60 minutes of suppressing protein synthesis. These data implicate pathogenic proteins with a short half-life that are rapidly depleted by inhibiting mRNA translation. In Aim 1 of this exploratory project, we will take advantage of genetic access to a subpopulation of L5 neurons to identify these proteins. If successful, this approach will yield a list of novel therapeutic targets specifically linked to aberrant protein synthesis in fragile X. In Aim 2, we will assess the generality of our findings in L5, and investigate the impact of this specific pathogenic mechanism on the function of V1 in awake mice. These experiments will yield novel functional measures of treatment efficacy in vivo that, if translated to humans, could be used as potential biomarkers of a specific class of pathophysiological mechanisms in fragile X and related disorders.