KNCQ Potassium Channels and Schizophrenia

描述(申请人提供)：精神分裂症是一种慢性精神障碍，具有破坏性和破坏性的个人、家庭和社会后果，影响约1.1%的18岁以上世界人口。在任何一年，超过240万美国人和世界上约5200万人患有与精神分裂症(SZ)相关的病理。SZ的病因尚不完全清楚，其复杂的神经生物学是缺乏有效治疗该疾病症状的部分原因。目前的药物和治疗方法可以改善一些疾病症状；然而，SZ的核心病理(阴性症状和认知障碍)不受影响。此外，目前的药物存在严重的副作用，限制了它们的使用 病人。因此，识别和了解有效治疗SZ阴性和认知症状的大脑机制仍然是一个关键的未得到满足的需求。我们发现脑KCNQ(KV7)电压门控钾通道是一种独特的信号机制，能够改善SZ的阴性症状和认知症状。这些离子通道在大脑中广泛表达，并关键位于与SZ功能障碍相关的脑区。KCNQ钾通道具有独特的功能特性，使其成为大脑中神经元和网络活动的重要调节器。我们的初步数据有力地表明，这些通道可以改善SZ动物模型的行为缺陷。在这项建议中，我们试图表征前额叶皮质KCNQ钾通道在与SZ相关的阴性和认知症状中的作用。此外，我们将使用新的多点电生理记录技术来研究正常和疾病状态下的脑网络活动，并确定KCNQ钾通道在调节其活动中的作用。因此，在目标1中，将使用脑内微量注射KCNQ通道激活剂和阻断剂来确定前额叶皮质通道在调节与SZ相关的异常行为中的作用。我们还将利用SZ(甲氧基甲醇醋酸酯，MAM)的发育动物模型来验证我们关于KCNQ通道作用的假设。在目标2中，我们将使用同时多细胞多点电生理记录在自由活动的认知任务动物的海马区和前额叶皮质，以表征这两个结构中的网络活动以及它们在控制和疾病状态下的相互作用(使用急性PCP动物模型)。此外，我们还将监测网络对KCNQ钾通道调制的反应。最后，我们将记录MAM处理的大鼠的海马区和前额叶皮质，以及它们对KCNQ钾通道调制的反应。这些研究将提供一个独特的机会，利用行为、细胞和神经元网络分析来研究重要的大脑信号机制KCNQ通道在SZ病理中的作用。这一研究项目的总体目标是支持NIMH的使命，促进精神障碍病因的研究和进步。

DESCRIPTION (provided by applicant): Schizophrenia is a chronic mental disorder with devastating and disruptive personal, family, and social consequences, which affects about 1.1% of the world population above 18 years of age. In any given year, more than 2.4 million Americans and about 52 million individuals in the world suffer from pathologies associated with schizophrenia (SZ). The etiology of SZ is not completely understood and its complex neurobiology has been partly responsible for the lack of treatments to effectively treat the disease symptoms. Current medications and treatments ameliorate some of the disease symptoms; however, core pathologies of SZ (negative symptoms and cognitive deficits) are not affected. In addition, current medications suffer from serious side effects that limit their use by patients. Therefore, there remains a critical unmet need to identify and understand brain mechanisms effective in treating the negative and cognitive symptoms of SZ. We have identified Brain KCNQ (Kv7) voltage-gated potassium channels as unique signaling mechanism capable of ameliorating the negative and cognitive symptoms of SZ. These ion channels are widely expressed in the brain and are critically located in brain regions associated with SZ dysfunctions. The KCNQ potassium channels possess unique functional properties that allow them to be important regulators of neuronal and network activity in the brain. Our preliminary data strongly suggest that these channels can ameliorate behavioral deficits in animal models of SZ. In this proposal, we seek to characterize the role of prefrontal cortex KCNQ potassium channels in negative and cognitive symptoms associated with SZ. In addition, we will use the novel technique of multisite electrophysiological recording to study brain network activity under normal and disease states and determine the role of KCNQ potassium channels in modulating their activity. Therefore, in Aim 1, intracerebral microinfusion of KCNQ channel activators and blockers will be used to ascertain the role of prefrontal cortex channels in regulating aberrant behaviors associated with SZ. We will also take advantage of a developmental animal model of SZ (Methylazoxymethanol acetate, MAM) to test our hypothesis on the role of KCNQ channels. In Aim 2, we will use simultaneous multicell multisite electrophysiological recording from hippocampus and prefrontal cortex of freely moving behaving animals engaged in a cognitive task to characterize the network activity in these two structures as well as their mutual interactions under control and disease states (using acute PCP animal model). In addition, we will monitor the network responses to modulation of KCNQ potassium channels. Lastly, we will record from hippocampus and prefrontal cortex of MAM treated rats and their response to modulation of KCNQ potassium channels. These studies will provide a unique opportunity to investigate the role of an important brain signaling mechanism, the KCNQ channel, in pathology of SZ using behavioral, cellular, and neuronal network analysis. The overall goal of this research project is in support of the NIMH mission to promote research and progress on the causes of mental disorders.