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：
10619581
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/10619581
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 Process Purkinje Cells Regulation Role Symptoms Synapses Testing Therapeutic Transgenic Mice Wild Type Mouse Work autism spectrum disorder behavioral phenotyping cell type cognitive disability comorbidity dystrophinopathy expectation genetic technology improved in vivo insight interdisciplinary approach mouse model nervous system disorder neural neural circuit novel pharmacologic prevent receptor 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.

项目摘要/摘要肌营养不良蛋白缺乏症发生在Duchenne肌肉营养不良（DMD）中，导致肌肉浪费。作为肌营养不良蛋白在大脑中表达，其缺乏也导致了DMD患者的神经系统症状。 DMD小鼠模型中小脑Purkinje细胞的抑制性突触连接较弱，并且受损的攀爬纤维诱发的可塑性。这意味着小脑功能障碍是导致的因素 DMD的神经病理生理。然而，小脑功能障碍最终如何解释DMD神经系统症状仍然不完全理解。增加证据表明可塑性门的重要性保持储备的学习能力。在Purkinje细胞中，可塑性感应的候选门控机制是对分子层中间神经元的抑制作用，它抑制了诱发的钙反应对攀爬纤维的反应激发触发了长期抑郁症（LTD）的诱因。因此，这项研究的目的是测试抑制性突触弱化和抑制性LTD的潜在协同作用确定在Purkinje细胞中专门在Purkinje细胞中提高GABAA受体反应能力是否会恢复高阈值为了塑性诱导，因此提供了一种潜在的治疗策略，可以改善小脑功能障碍。我们将采用一种多学科的方法，包括在体内使用和体内功能记录 Purkinje-Cell自主性肌营养不良蛋白缺乏小鼠，细胞型特异性神经药物扰动和行为分析。通过两个目标，我们将测试异常神经之间的相关和因果关系电路响应能力，虚假可塑性和小脑学习异常。这些目标的完成将对可塑性调节的新见解，DMD中神经系统障碍的病因以及潜力治疗这种疾病的小脑相关症状的途径。