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Cerebellar pathology in the absence of plasticity gating

缺乏可塑性门控的小脑病理学

基本信息

批准号：
10440493
负责人：
Jason M Christie
金额：
$ 45.54万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10440493
关键词：
Affect Agreement Animals Attention deficit hyperactivity disorder Automobile Driving Behavior Behavioral Brain Brain Diseases Calcium Calcium Signaling Cells Cerebellar Diseases Cerebellum Chronic Conflict (Psychology)Custom Data Dendrites Disease Disinhibition Duchenne muscular dystrophy Dystrophin Engineering Etiology Exhibits Fiber Fire - disasters Functional disorder Goals Health Human Impairment Inferior Inhibitory Synapse Interneurons Learning Link Long-Term Depression Mediating Molecular Molecular Genetics Mus Muscular Atrophy Neurobiology Neurologic Neurologic Symptoms Olives - dietary Outcome Pathologic Pathology Patients Performance Pharmaceutical Preparations Pharmacology Process Purkinje Cells Regulation Role Symptoms Synapses Testing Therapeutic Transgenic Mice Wild Type Mouse Work autism spectrum disorder base behavior test behavioral phenotyping cell type cognitive disability comorbidity dystrophinopathy expectation genetic technology improved in vivo insight interdisciplinary approach mouse model nervous system disorder neural circuit novel prevent receptor relating to nervous system response synaptic function therapeutic target therapy development treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Dystrophin deficiency, which occurs in Duchenne muscular dystrophy (DMD), results in muscle wasting. As dystrophin is expressed in the brain, its deficiency also contributes to neurological symptoms in DMD patients. Cerebellar Purkinje cells in mouse models of DMD have weaker inhibitory synaptic connections and compromised climbing-fiber-evoked plasticity. This implicates cerebellar dysfunction as a contributing factor to the neurological pathophysiology of DMD. Yet, how cerebellar dysfunction ultimately explains DMD neurological symptoms remains incompletely understood. Increasing evidence points to the importance of plasticity gating to maintain a reserve capacity for learning. In Purkinje cells, a candidate gating mechanism of plasticity induction is inhibition from molecular layer interneurons, which suppresses the evoked calcium response to climbing fiber excitation that triggers induction of long-term depression (LTD). Therefore, the objective of this study is to test for a potential synergistic role of inhibitory synapse weakening and compromised LTD in dystrophinopathy and determine if increasing GABAA receptor responsiveness specifically in Purkinje cells restores a high threshold for plasticity induction and thus provide a potential therapeutic strategy to ameliorate cerebellar dysfunction. We will employ a multidisciplinary approach encompassing the use of ex vivo and in vivo functional recordings in Purkinje-cell-autonomous dystrophin-deficient mice, cell-type specific neuropharmacological perturbations, and behavioral analyses. Through two aims, we will test correlative and causative links between aberrant neural circuit responsiveness, spurious plasticity, and cerebellar learning abnormalities. Completion of these aims will contribute novel insights into plasticity regulation, the etiology of neurological impairment in DMD, and potential avenues for treating cerebellum-related symptoms of this disorder.

项目总结/摘要肌营养不良蛋白缺乏，发生在杜氏肌营养不良症（DMD），导致肌肉萎缩。作为虽然肌营养不良蛋白在脑中表达，但其缺乏也有助于DMD患者的神经症状。 DMD小鼠模型中的小脑浦肯野细胞具有较弱的抑制性突触连接，攀爬纤维诱发的可塑性受损这表明小脑功能障碍是导致 DMD的神经病理生理学然而，小脑功能障碍如何最终解释DMD神经学症状仍然不完全清楚。越来越多的证据表明可塑性门控对保持学习的储备能力。在浦肯野细胞中，可塑性诱导的候选门控机制是来自分子层中间神经元的抑制，其抑制对攀爬纤维的诱发钙反应激发诱发长期抑郁（LTD）。因此，本研究的目的是测试在抗肌萎缩蛋白病中抑制性突触弱化和受损LTD的潜在协同作用，确定是否增加GABAA受体的反应性，特别是在浦肯野细胞恢复高阈值从而为改善小脑功能障碍提供了潜在的治疗策略。我们将采用多学科方法，包括使用离体和体内功能记录，浦肯野细胞自主性肌营养不良蛋白缺陷小鼠，细胞类型特异性神经药理学扰动，行为分析通过两个目标，我们将测试相关的和因果关系之间的异常神经元电路反应性、假性可塑性和小脑学习异常。实现这些目标将有助于对可塑性调节，DMD神经功能损害的病因学和潜在的治疗这种疾病的小脑相关症状的途径。