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Does a Common Mechanism Trigger Attacks in Episodic Ataxia Type 2?

2 型发作性共济失调是否有共同机制引发发作？

基本信息

批准号：
8835728
负责人：
Ariel Vitenzon
金额：
$ 4.27万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-21 至 2017-09-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835728
关键词：
Action Potentials Adrenergic Agents Adrenergic Receptor Affect Agonist Alcohol consumption Alcohols Animals Ataxia Automobile Driving Behavior Brain Caffeine Calcium Calcium Channel Calmodulin Cells Cerebellum Coupling Data Dyskinetic syndrome Dystonia Emotional Stress Ethanol Exhibits Familial Hemiplegic Migraine Fire - disasters Frequencies Functional disorder Genes Goals In Vitro Intervention Ion Channel Knowledge Lead Link Measures Modeling Molecular Molecular Biology Motor Movement Mus Muscle Mutation Nervous system structure Neurons Norepinephrine Output P-Q type voltage-dependent calcium channel Patients Pattern Pharmaceutical Preparations Phosphorylation Physiological Probability Protein Isoforms Purkinje Cells Q-Type Calcium Channels Quality of life Receptor Activation Rodent Rodent Model Stress Symptoms Techniques Testing Work acute stress adrenergic behavior test calcium-activated potassium channel small-conductance casein kinase II drug development improved in vivo loss of function mutation mouse model nervous system disorder new therapeutic target prevent public health relevance research study response stressor voltage

项目摘要

DESCRIPTION (provided by applicant): Episodic ataxia type 2 (EA2) is a neurological disorder caused by mutations in the CACNA1A gene encoding for the pore forming α-1a subunit of the P/Q type voltage gated calcium channel (Cav2.1). EA2 patients exhibit episodic attacks of severe ataxia triggered by different stressors such as, caffeine and alcohol consumption and physical or emotional stress. Previous work in our lab has shown that the motor attacks in a rodent EA2 model, tottering, are due to an aberrant output from the cerebellum driven by erratic burst firing of Purkinje cells (PC). The tottering mouse is a well-established rodent model of EA2. They carry a spontaneous mutation in the CACNA1A gene rendering the Cav2.1 channel non-functional and exhibit motor attacks induced by stress, caffeine and alcohol similar to EA2 patients. Interestingly, all three triggers result in the same change in the firing pattern of PCs n these animals, suggesting a common converging mechanism. PCs are intrinsically active and in vivo exhibit tonic firing at 50 spikes per second. This firing pattern is partially governed by the tight coupling of Cav2.1 channels to the small conductance calcium activated potassium channels (SK2) that help regulate the intrinsic activity of these cells. It has been shown that blocking SK2 channels promotes burst firing of wild type PCs, whereas activating them in the cerebellum of tottering mice restores PC regularity and alleviates attacks induced by caffeine or stress. Give that the calcium current through Cav2.1 channels in tottering mice is already diminished and that SK2 channels are gated by Cav2.1 dependent calcium, a further reduction in SK2 activity could be the cause for the observed bursting of PCs during attacks. Indeed, preliminary data from our lab suggests that all three triggers converge on the modulation of SK2 activity. Interestingly, this modulation seems to be dependent on increases in norepinephrine (NE) levels in the cerebellum, a phenomenon known to occur in response to stress, caffeine and alcohol. Thus, our working hypothesis is that all three triggers functionally converge to reduce open probability of PCs SK2 channels via a NE dependent mechanism. My main goal in this proposal is to further delineate the mechanism driving the attacks in tottering mice by perturbing SK2 gating and asking how it will affect attacks. I plan to achieve this by combining electrophysiological techniques together with molecular biology and behavioral tests. This powerful approach will allow me to link molecular mechanisms, physiological function and behavior.