Mechanistic insights of cortical hyperexcitability in ALS

项目摘要/摘要 肌萎缩侧索硬化症(ALS)是一种毁灭性的神经退行性疾病，由上半部分的缺失引起。 运动神经元降低，导致进行性肌肉无力和瘫痪。许多改变了的分子和 细胞通路被认为与疾病的发病机制有关。然而，确定哪些是原因 仍然具有挑战性，在过去的几十年里，许多临床试验都失败了。一种解释是 不成功的临床干预是一旦死亡就很难挽救濒临死亡的运动神经元 触发，意味着必须在疾病的早期实施治疗干预。几个月前 临床上，肌萎缩侧索硬化症患者通常会出现束状痉挛和抽筋(即自发性和持续性 肌肉抽动)，表明神经活动和兴奋性增加。事实上，中国的神经生理学研究 患有肌萎缩侧索硬化症相关基因突变的患者和啮齿动物模型已经发现， 具体地说，运动皮质过度兴奋，是最早的病理之一。最近，两项研究表明 运动皮质中的上皮质脊髓运动神经元(CSMN)在低运动中起重要作用 表达人SOD1突变的转基因小鼠的神经元死亡。因此，我们假设CSMN 高兴奋性可能是ALS发病机制之一。我们建议利用最近开发的增强子驱动的病毒 允许细胞特异性靶向的工具1)执行尖端的化学遗传学以调节神经元活动 确定在症状前期晚期抑制CSMN的过度兴奋性是否可以缓解ALS- SOD1G93A小鼠的相关行为和病理缺陷，以及2)鉴定细胞特异性改变的分子 导致运动皮质过度兴奋的通路。本研究具有重要的现实意义 针对ALS患者这一早期临床异常的治疗。

PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the loss of upper and lower motor neurons, leading to progressive muscle weakness and paralysis. Many altered molecular and cellular pathways have been implicated in disease pathogenesis. However, determining which are causative remains challenging, and many clinical trials have failed in the last few decades. One explanation for the unsuccessful clinical interventions is the difficulty of rescuing dying motor neurons once death has been triggered, meaning that therapeutic interventions must be implemented early in the disease. Months before clinical onset, ALS patients often experience fasciculations and cramps (i.e., spontaneous and persistent muscle twitching), suggesting increased neural activity and excitability. Indeed, neurophysiological studies in patients and rodent models with ALS-associated genetic mutations have identified that circuit dysfunction, specifically motor cortex hyperexcitability, are among the earliest pathologies. Recently, two studies suggested that upper corticospinal motor neurons (CSMN) in the motor cortex play an essential role in the low motor neuron death of transgenic mice expressing human SOD1 mutations. We thus hypothesize that CSMN hyperexcitability might drive ALS pathogenesis. We propose to utilize recently developed enhancer-driven viral tools that allow cell-specific targeting to 1) perform cutting-edge chemogenetics to modulate neuronal activity to determine whether dampening CSMN hyperexcitability in the late pre-symptomatic stage can mitigate ALS- related behavioral and pathological deficits in SOD1G93A mice, and 2) identify cell-specific altered molecular pathways leading to motor cortex hyperexcitability. This study has significant implications in developing therapeutics targeting this early clinical abnormality in ALS patients.