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: 8066946
• 负责人: JOHN P ADELMAN
• 金额: $ 18.87万
• 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/8066946
• 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; Health; 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; 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）：许多中枢和外周神经元中动作电位后的缓慢后超极化（sAHP）是由于电压无关的、Ca2+激活的K+通道的激活所致。海马 CA1 神经元已成为研究 sAHP 和潜在电流 IsAHP 的模型。过去二十年的研究结果表明，sAHP 对神经元内在兴奋性具有深远的影响，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目标之一，该系统参与调节睡眠-觉醒周期、唤醒、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 在学习后会降低，从而增加内在兴奋性。此外，(I)sAHP 随着年龄的增长而增加，从而降低了内在的兴奋性，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 也出现类似的增加。 (I)sAHP 通道的定义为：Ca2+ 依赖性、电压无关性、K+ 选择性和不变的慢激活动力学。海马 CA1 和 CA3、皮质 II-III 层、（外侧）杏仁核和（中线）丘脑记录了难以区分的 (I)sAHP。有人建议 SK 通道和 M 通道形成 (I)sAHP 通道，但存在大量相互矛盾的证据。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。我们使用生物信息基因组分析结合克隆通道的功能特征、基因敲除小鼠的结果以及所有 K+ 通道基因的详细细胞类型表达数据来确定 (I)sAHP 通道的 2 个高优先级候选者。我们建议结合使用分子生物学和电生理学技术来测试这些候选者并鉴定编码 (I)sAHP 通道的成孔亚基的克隆。 确定 (I)sAHP 通道的身份将为治疗多种中枢疾病（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大的靶标。 公共健康相关性：慢后超极化 (AHP) 通道调节许多中枢神经元的内在兴奋性，其活动对于正常的睡眠-觉醒周期、唤醒、注意力以及调节感觉处理、行为、情绪和记忆巩固非常重要。我们将克隆慢速 AHP 通道并定义其必需的组件。确定慢 AHP 通道的身份将为治疗多种中枢疾病（如阿尔茨海默氏病、精神分裂症、癫痫、注意力缺陷综合症和睡眠障碍）以及正常衰老过程中的认知障碍的治疗方法提供强大的目标。