Molecular definition of the slow AHP channels in CA1 neurons

CA1 神经元慢 AHP 通道的分子定义

• 批准号: 7979132
• 负责人: JOHN P ADELMAN
• 金额: $ 23.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979132
• 关键词: Action Potentials; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amygdaloid structure; Area; Arousal; Attention; Behavior; Bioinformatics; Biological; Calcium-Activated Potassium Channel; Candidate Disease Gene; Characteristics; Chinese Hamster Ovary Cell; Coupled; Data; Dependence; Dominant-Negative Mutation; Emotions; Epilepsy; Frequencies; Future; Genes; Genome; Hippocampus (Brain); Impaired cognition; Impairment; Injection of therapeutic agent; Kinetics; Knock-out; Knockout Mice; Lateral; Learning; Measures; Memory; Molecular; Neurons; Neurotransmitters; Pathology; Peripheral; Play; Potassium Channel; Proteomics; Role; Schizophrenia; Sensory Process; Sleep Disorders; Sleep Wake Cycle; Small Interfering RNA; Study models; System; Techniques; Testing; Thalamic structure; Transgenic Mice; Viral; Virus; Whole-Cell Recordings; Work; age related; base; cell type; deficit syndrome; normal aging; public health relevance; research study; therapeutic target; voltage

DESCRIPTION (provided by applicant): The slow afterhyperpolarization (sAHP) that follows an action potential in many central and peripheral neurons is due to the activation of voltage-independent, Ca2+-activated K+ channels. Hippocampal CA1 neurons have served as models for studying the sAHP and the underlying current, the IsAHP. The results of studies performed over the past two decades show that the sAHP has a profound influence on neuronal intrinsic excitability, being responsible for spike-frequency adaptation that regulates burst frequency. The sAHP is one of the principal targets for the ascending modulatory neurotransmitter systems that are involved in regulating the sleep-wake cycle, arousal, attention, and in modulating sensory processing, behaviors, emotions and memory consolidation. Importantly, the (I)sAHP decreases following learning, increasing intrinsic excitability. In addition, the (I)sAHP increases with age, reducing intrinsic excitability, and this age-related increase plays an integral role in the learning impairments that accompany normal aging. A similar increase in the (I)sAHP occurs in Alzheimer's disease models. The (I)sAHP channels are defined by: Ca2+-dependence, voltage-independence, K+-selectivity, and invariant slow activation kinetics. Indistinguishable (I)sAHPs have been recorded from hippocampal CA1and CA3, layers II-III of the cortex, (lateral) amygdala, and (midline) thalamus. SK channels and M-channels have been suggested to form the (I)sAHP channels, but there is abundant contradictory evidence. Therefore, despite decades of work, the molecular identity of the (I)sAHP channels remains to be determined. We have used bioinformatic genome analysis coupled with the functional characteristics of cloned channels, results from knockout mice, and detailed cell-type expression data for all K+ channel genes to identify 2 high priority candidates for the (I)sAHP channels. We propose to use a combination of molecular biological and electrophysiological techniques to test these candidates and identify clones encoding the pore-forming subunits of the (I)sAHP channels. Determining the identities of the (I)sAHP channels will provide a powerful target for therapeutic approaches to multiple central pathologies such as Alzheimer's disease, schizophrenia, epilepsy, attention deficit syndrome, and sleep disorders, as well as for cognitive impairment during normal aging. PUBLIC HEALTH RELEVANCE: The slow afterhyperpolization (AHP) channels regulate intrinsic excitability in many central neurons, and their activity is important for normal sleep-wake cycle, arousal, attention, and in modulating sensory processing, behaviors, emotions and memory consolidation. We will clone the slow AHP channels and define their requisite components. Determining the identities of the slow AHP channels will provide a powerful target for therapeutic approaches to multiple central pathologies such as Alzheimer's disease, schizophrenia, epilepsy, attention deficit syndrome, and sleep disorders, as well as for cognitive impairment during normal aging.

描述（由申请人提供）：在许多中枢和外周神经元中，动作电位之后的缓慢后超极化（sAHP）是由于电压无关的、Ca2+激活的K+通道的激活。海马CA1神经元被用作研究sAHP和潜在电流IsAHP的模型。过去二十年的研究结果表明，sAHP对神经元的内在兴奋性有深远的影响，它负责调节突发频率的尖峰频率适应。sAHP是上行调节神经递质系统的主要靶点之一，该系统参与调节睡眠-觉醒周期、觉醒、注意力以及调节感觉处理、行为、情绪和记忆巩固。重要的是，(I)sAHP在学习后减少，增加了内在兴奋性。此外，(I)sAHP随着年龄的增长而增加，内在兴奋性降低，这种与年龄相关的增加在伴随正常衰老的学习障碍中起着不可或缺的作用。在阿尔茨海默病模型中，(I)sAHP也出现了类似的增加。(I)sAHP通道的定义是：Ca2+依赖性，电压不依赖性，K+选择性和不变的慢活化动力学。难以区分的(I)在海马ca1和CA3、皮层II-III层、（侧）杏仁核和（中线）丘脑中记录到了sahp。SK通道和m通道被认为形成了(I)sAHP通道，但有大量的矛盾证据。因此，尽管经过数十年的研究，(I)sAHP通道的分子身份仍有待确定。我们使用生物信息学基因组分析，结合克隆通道的功能特征，敲除小鼠的结果，以及所有K+通道基因的详细细胞型表达数据，确定了2个高优先级的(I)sAHP通道候选者。我们建议结合分子生物学和电生理学技术来测试这些候选基因，并鉴定编码(I)sAHP通道成孔亚基的克隆。确定(I)sAHP通道的身份将为多种中枢疾病（如阿尔茨海默病、精神分裂症、癫痫、注意力缺陷综合征和睡眠障碍）以及正常衰老过程中的认知障碍的治疗方法提供强有力的靶点。