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

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干扰和 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。

项目成果

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Jason M Christie其他文献

Jason M Christie的其他文献

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{{ truncateString('Jason M Christie', 18)}}的其他基金

Motor Memory Storage in the Cerebellum
小脑中的运动记忆存储
  • 批准号:
    10338677
  • 财政年份:
    2021
  • 资助金额:
    $ 45.54万
  • 项目类别:
AnteroTag, a Novel Method for Trans-Synaptic Delivery of Active Agents to Map and Modify Anterograde Populations
AnteroTag,一种跨突触传递活性剂以绘制和修改顺行群体的新方法
  • 批准号:
    10258693
  • 财政年份:
    2021
  • 资助金额:
    $ 45.54万
  • 项目类别:
Cerebellar pathology in the absence of plasticity gating
缺乏可塑性门控的小脑病理学
  • 批准号:
    10289334
  • 财政年份:
    2021
  • 资助金额:
    $ 45.54万
  • 项目类别:
Cerebellar pathology in the absence of plasticity gating
缺乏可塑性门控的小脑病理学
  • 批准号:
    10619581
  • 财政年份:
    2021
  • 资助金额:
    $ 45.54万
  • 项目类别:
Motor Memory Storage in the Cerebellum
小脑中的运动记忆存储
  • 批准号:
    10600069
  • 财政年份:
    2021
  • 资助金额:
    $ 45.54万
  • 项目类别:
Motor Memory Storage in the Cerebellum
小脑中的运动记忆存储
  • 批准号:
    10469662
  • 财政年份:
    2021
  • 资助金额:
    $ 45.54万
  • 项目类别:
Organization of inhibition in the cerebellar cortex
小脑皮质的抑制组织
  • 批准号:
    10877237
  • 财政年份:
    2020
  • 资助金额:
    $ 45.54万
  • 项目类别:
Organization of inhibition in the cerebellar cortex
小脑皮质的抑制组织
  • 批准号:
    10349928
  • 财政年份:
    2020
  • 资助金额:
    $ 45.54万
  • 项目类别:
Regulation of instructive signaling in the cerebellum
小脑指导信号的调节
  • 批准号:
    10237314
  • 财政年份:
    2018
  • 资助金额:
    $ 45.54万
  • 项目类别:
Regulation of instructive signaling in the cerebellum
小脑指导信号的调节
  • 批准号:
    9977802
  • 财政年份:
    2018
  • 资助金额:
    $ 45.54万
  • 项目类别:

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    2234506
  • 财政年份:
    2023
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