Voltage-gated ion channels and synaptic integration by cerebellar Purkinje cells

小脑浦肯野细胞的电压门控离子通道和突触整合

• 批准号: 7616380
• 负责人: Maria-Johanna Dizon
• 金额: $ 4.12万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-13 至 2012-01-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616380
• 关键词: Ataxia; Calcium Spikes; Cells; Cerebellar cortex structure; Cerebellum; Dendrites; Disease; Electrophysiology (science); Equilibrium; Exhibits; Gated Ion Channel; Glutamates; Goals; Hereditary Disease; Individual; Investigation; Membrane Proteins; Monitor; Motor; Movement; Nature; Neurons; Output; Pharmacology; Physiological; Posture; Preparation; Process; Property; Purkinje Cells; Rattus; Research; Role; Shapes; Slice; Spinocerebellar Ataxias; Stimulus; Symptoms; Synapses; Synaptic Potentials; Testing; Toxin; Type 6 Spinocerebellar Ataxia; Work; defined contribution; extracellular; granule cell; interest; neuroregulation; patch clamp; presynaptic; research study; response; voltage; voltage gated channel

DESCRIPTION (provided by applicant): The role of voltage-gated channels in shaping synaptic integration in cerebellar Purkinje cells is little understood. Examination of their functional properties and interactions is of critical interest since many debilitating hereditary diseases presenting cerebellar symptoms, including episodic ataxia types 1 (EA1) and 2 (EA2), and spinocerebellar ataxia type 6 (SCA6), are disorders of these membrane proteins. The overall goal of this research plan is to define the contributions of select voltage-gated conductances to the integration of excitatory synaptic inputs by Purkinje cells. Purkinje cells integrate a massive convergence of excitatory and inhibitory inputs and are the sole output of the cerebellar cortex. They are thus the main computational units of the cerebellum, ultimately enabling proper motor coordination, posture, and balance. Prior work in the lab established that Purkinje cells linearly encode the strength of their presynaptic glutamatergic granule cell inputs in their maximum post-stimulus firing rate. This was surprising considering that Purkinje cells exhibit active dendritic calcium spikes brought about by various dendritic voltage-gated conductances, which are inherently nonlinear. How is the activity of voltage-gated channels in Purkinje cells choreographed to allow for the linear summation of their granule cell inputs? We propose two aims to begin answering this question: 1) To noninvasively assess the contribution of select voltage-gated ion channels to the granule cell input-Purkinje cell output function; and 2) To test the hypothesis that active dendritic conductances are balanced to achieve the linear granule cell input-Purkinje cell output relationship. We will accomplish this through experiments combining extracellular and whole-cell patch clamp electrophysiology, glutamate uncaging, and pharmacology applied to a rat cerebellar slice preparation. These investigations are not only crucial to understanding neural control of movement and the mechanisms underlying ataxia, but also will help elucidate neuronal computational processes in general.

描述（由申请人提供）：电压门控通道在塑造小脑浦肯野细胞突触整合中的作用知之甚少。检查它们的功能特性和相互作用至关重要，因为许多呈现小脑症状的衰弱遗传性疾病，包括阵发性共济失调 1 型 (EA1) 和 2 (EA2) 以及脊髓小脑共济失调 6 型 (SCA6)，都是这些膜蛋白的疾病。该研究计划的总体目标是确定选定的电压门控电导对浦肯野细胞兴奋性突触输入整合的贡献。浦肯野细胞整合了大量的兴奋性和抑制性输入，是小脑皮质的唯一输出。因此，它们是小脑的主要计算单元，最终实现正确的运动协调、姿势和平衡。实验室之前的工作表明，浦肯野细胞以最大刺激后放电率线性编码其突触前谷氨酸能颗粒细胞输入的强度。考虑到浦肯野细胞表现出由各种树突电压门控电导引起的活跃树突钙尖峰，这些电导本质上是非线性的，这是令人惊讶的。浦肯野细胞中的电压门控通道的活动是如何设计的，以允许其颗粒细胞输入的线性求和？我们提出两个目标来开始回答这个问题：1）无创地评估选定的电压门控离子通道对颗粒细胞输入-浦肯野细胞输出功能的贡献； 2) 检验活性树突电导平衡以实现线性颗粒细胞输入-浦肯野细胞输出关系的假设。我们将通过结合细胞外和全细胞膜片钳电生理学、谷氨酸解笼锁和应用于大鼠小脑切片制备的药理学的实验来实现这一目标。这些研究不仅对于理解运动的神经控制和共济失调的机制至关重要，而且还将有助于阐明一般的神经元计算过程。