Molecular definition of the slow AHP channels in CA1 neurons

描述(申请人提供)：在许多中枢和外周神经元中跟随动作电位的慢后超极化(SAHP)是由于电压不依赖的、钙激活的K通道的激活。海马区CA1神经元已被用作研究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，负责调节爆发频率的尖峰频率适应。SAHP是上行调节性神经递质系统的主要靶点之一，参与调节睡眠-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在学习后降低，增加了内在的兴奋性。此外，(I)SAHP随着年龄的增长而增加，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而来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也有类似的增加。(I)SAHP通道定义为：钙依赖性、电压非依赖性、钾选择性和不变的慢激活动力学。无法区分(1)在海马CA1和CA3、皮质II-III层、(外侧)杏仁核和(中线)丘脑记录到sAHPs。SK通道和M通道被认为是(I)SAHP通道，但有大量相互矛盾的证据。因此，尽管进行了几十年的工作，(I)SAHP通道的分子同一性仍有待确定。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，来自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，确定了(I)SAHP通道的两个高优先级候选。我们建议使用分子生物学和电生理技术的组合来测试这些候选基因，并识别编码(I)SAHP通道的成孔亚基的克隆。确定(I)SAHP通道的身份将为多种中枢疾病的治疗方法提供一个强大的靶点，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，以及正常衰老期间的认知障碍。 与公共健康相关：慢后超极化(AHP)通道调节许多中枢神经元的内在兴奋性，它们的活动对正常的睡眠-觉醒周期、唤醒、注意力以及调节感觉处理、行为、情绪和记忆巩固至关重要。我们将克隆慢速AHP通道并定义它们的必要组件。确定慢AHP通道的身份将为多种中枢疾病的治疗方法提供强大的靶点，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，以及正常衰老期间的认知障碍。

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.