Cerebellar pathology in the absence of plasticity gating

项目摘要/摘要 Duchenne肌营养不良症(DMD)中的肌营养不良蛋白缺乏会导致肌肉萎缩。AS Dstrophin在大脑中表达，它的缺乏也导致DMD患者的神经症状。 DMD模型小鼠小脑浦肯野细胞抑制性突触连接较弱， 受损的攀爬纤维引起的可塑性。这意味着小脑功能障碍是一个促成因素。 DMD的神经病理生理学。然而，小脑功能障碍最终如何解释DMD神经学 症状仍不完全清楚。越来越多的证据表明，塑性浇注对 保持学习的后备能力。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，它抑制了对攀升纤维的诱发钙反应 引发长期抑郁(LTD)的兴奋。因此，本研究的目的是验证 抑制性突触减弱和受损的LTD在营养不良和营养不良中的潜在协同作用 确定在浦肯野细胞中特异性增加GABAA受体反应性是否能恢复高阈值 用于可塑性诱导，从而提供一种潜在的治疗策略来改善小脑功能障碍。我们 将采用多学科方法，包括使用体外和体内功能录音在 浦肯野细胞自主性营养不良蛋白缺陷小鼠，细胞类型特异性神经药理学干扰，以及 行为分析。通过两个目标，我们将检验异常神经之间的相关和因果联系 回路反应、假性可塑性和小脑学习异常。完成这些目标将 对可塑性调节、DMD神经损害的病因和潜力提供新的见解 治疗这种疾病的小脑相关症状的途径。

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.