Calcium-activated potassium currents in cerebellar Purkinje neurons

小脑浦肯野神经元中钙激活的钾电流

• 批准号: 8127505
• 负责人: Mark Daniel Benton
• 金额: $ 2.18万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127505
• 关键词: ALPP; Action Potentials; Agonist; Apamin; Ataxia; Behavior; Brain; Brain region; Buffers; Calcium; Calcium Channel; Calcium Signaling; Cells; Cerebellar Diseases; Cerebellar cortex structure; Cerebellum; Chlorzoxazone; Coupled; Data; Disease; Equilibrium; Familial Hemiplegic Migraine; Fire - disasters; Frequencies; Functional disorder; Gene Mutation; Genes; Goals; Hereditary Disease; Human; Ion Channel; Ions; Kinetics; Laboratories; Lead; Measures; Motor; Mus; Mutant Strains Mice; Mutation; Neurons; Normal Cell; Output; P-Type Calcium Channels; Pathology; Pattern; Pharmaceutical Preparations; Physiology; Potassium; Purkinje Cells; Resistance; Shapes; Spinocerebellar Ataxias; Synapses; Testing; Therapeutic; Training; Type 6 Spinocerebellar Ataxia; Work; abstracting; iberiotoxin; insight; mutant; nervous system disorder; research study; voltage; voltage clamp; voltage gated channel

DESCRIPTION (provided by applicant): Abstract Purkinje neurons, the principal projection neurons of the cerebellar cortex, fire high frequency action potentials in the absence of synaptic input. Voltage-gated calcium (Ca) and calcium-activated potassium (KCa) channels contribute to the regularity of this spontaneous activity. Ca channel mutations can cause a number of genetic disorders, including both episodic and spinocerebellar ataxias, as well as familial hemiplegic migraine. Thus, studying Ca and KCa channel physiology has the potential to increase our understanding of the pathology underlying several different disease states. Our recent work has shown that during spontaneous firing, Purkinje cell Ca currents are remarkably stable in amplitude. This feature distinguishes them from many neurons throughout the brain, in which sustained high-frequency activity causes Ca currents to both facilitate and inactivate, resulting in significant changes in the amount of Ca that enters the cell during an action potential. Importantly, Purkinje cell Ca currents have the capacity for modulation, but facilitation and inactivation are balanced. In our proposed experiments, we will examine how two downstream targets of Ca influx, the big (BK) and small (SK) conductance KCa channels, respond to high-frequency stimulation. We will make whole cell voltage clamp recordings from dissociated mouse Purkinje neurons and test whether BK and SK currents filter or amplify the small changes in the Ca currents. Next, we will measure the amplitude and kinetics of these currents when activated by the cells' own action potential waveform. Finally, we will examine SK currents in the leaner mouse, which has a mutant Ca channels and is ataxic. Together, these data will help us to understand how Ca signaling shapes the normal activity of Purkinje cells, and by extension, how disruptions lead to disease. ) PUBLIC HEALTH RELEVANCE: This project examines the cellular mechanisms underlying electrical activity in Purkinje cells of the cerebellum, a region of the brain important for motor coordination. Genetic mutations can cause these neurons to behave abnormally, which is thought to cause multiple forms of ataxia. Our goal is to understand how the electrical activity in Purkinje neurons is regulated, which promises to provide insight into therapeutic treatments for cerebellar disorders.)

描述（由申请人提供）：摘要浦肯野神经元，小脑皮质的主要投射神经元，在没有突触输入的情况下激发高频动作电位。电压门控钙（Ca）和钙激活钾（KCa）通道有助于这种自发活动的规律性。钙离子通道突变可引起许多遗传性疾病，包括发作性和脊髓小脑性共济失调，以及家族性偏瘫性偏头痛。因此，研究Ca和KCa通道生理学有可能增加我们对几种不同疾病状态的病理学的理解。我们最近的工作表明，在自发放电，浦肯野细胞钙电流的幅度是非常稳定的。这一特征将它们与整个大脑中的许多神经元区分开来，在这些神经元中，持续的高频活动导致Ca电流既促进又抑制，从而导致在动作电位期间进入细胞的Ca量发生显着变化。重要的是，浦肯野细胞钙电流具有调节能力，但易化和失活是平衡的。在我们提出的实验中，我们将研究钙内流的两个下游目标，大（BK）和小（SK）电导KCa通道，如何响应高频刺激。我们将从分离的小鼠浦肯野神经元进行全细胞电压钳记录，并测试BK和SK电流是否过滤或放大Ca电流的微小变化。接下来，我们将测量这些电流在被细胞自身的动作电位波形激活时的振幅和动力学。最后，我们将检查SK电流在瘦小鼠，这有一个突变的钙通道，是共济失调。总之，这些数据将帮助我们了解钙信号是如何影响浦肯野细胞的正常活动的，并进一步了解干扰是如何导致疾病的。) 公共卫生关系：本项目研究小脑浦肯野细胞电活动的细胞机制，小脑是大脑中对运动协调很重要的区域。基因突变会导致这些神经元行为异常，这被认为会导致多种形式的共济失调。我们的目标是了解浦肯野神经元的电活动是如何调节的，这有望为小脑疾病的治疗提供见解。