KNCQ Potassium Channels and Schizophrenia

KNCQ 钾通道和精神分裂症

• 批准号: 8824412
• 负责人: MOHAMMADHOSSEIN BEHNAM GHASEMZADEH
• 金额: $ 23.56万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824412
• 关键词: 18 year old; Acute; Address; Adverse effects; Affect; Age; American; Animal Model; Animals; Attention; Behavior; Behavioral; Behavioral Symptoms; Brain; Brain region; Chronic; Clinical Trials; Cognitive; Cognitive deficits; Complex; Data; Databases; Delusions; Development; Disease; Disease model; Effectiveness; Etiology; Family; Functional disorder; Future; Goals; Hallucinations; Health; Hippocampus (Brain); Human; Individual; Ion Channel; Lead; Mediating; Memory; Memory impairment; Mental disorders; Methylazoxymethanol Acetate; Mission; Modeling; Monitor; National Institute of Mental Health; Neurobehavioral Manifestations; Neurobiology; Neurons; Pathology; Pathway Analysis; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phencyclidine; Play; Population; Positioning Attribute; Potassium Channel; Prefrontal Cortex; Property; Rattus; Research; Research Project Grants; Rodent; Role; Schizophrenia; Signal Transduction; Speech; Structure; Symptoms; Techniques; Testing; Therapeutic; Voltage-Gated Potassium Channel; Withdrawal; Work; base; channel blockers; cognitive function; disorder control; effective therapy; expectation; improved; information processing; novel; preclinical study; public health relevance; response; social; therapy development

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.

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岁以上的世界人口。在任何给定的一年中，超过240万美国人和世界上约5200万个体患有与精神分裂症（SZ）相关的病理。SZ的病因尚未完全了解，其复杂的神经生物学部分原因是缺乏有效治疗疾病症状的治疗方法。目前的药物和治疗改善了一些疾病症状;然而，SZ的核心病理（阴性症状和认知缺陷）不受影响。此外，目前的药物具有严重的副作用，这限制了它们的使用， 患者因此，仍然存在识别和理解有效治疗SZ的阴性和认知症状的脑机制的关键未满足的需求。我们已经确定脑KCNQ（Kv 7）电压门控钾通道作为能够改善SZ的负性和认知症状的独特信号传导机制。这些离子通道在大脑中广泛表达，并且关键地位于与SZ功能障碍相关的大脑区域。KCNQ钾通道具有独特的功能特性，使其成为脑中神经元和网络活动的重要调节剂。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。在这个提议中，我们试图描述前额叶皮层KCNQ钾通道在与SZ相关的阴性和认知症状中的作用。此外，我们将使用多位点电生理记录的新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，脑内微输注KCNQ通道激活剂和阻断剂将用于确定前额叶皮层通道在调节与SZ相关的异常行为中的作用。我们还将利用SZ（甲基偶氮甲醇乙酸酯，MAM）的发育动物模型来测试我们对KCNQ通道作用的假设。在目标2中，我们将使用来自参与认知任务的自由移动行为动物的海马和前额叶皮层的同时多细胞多位点电生理记录来表征这两个结构中的网络活动以及在控制和疾病状态下它们的相互作用（使用急性PCP动物模型）。此外，我们将监测网络对KCNQ钾通道调节的反应。最后，我们将记录MAM处理的大鼠海马和前额叶皮层对KCNQ钾通道调节的反应。这些研究将提供一个独特的机会，调查一个重要的大脑信号传导机制，KCNQ通道，在病理学SZ使用行为，细胞和神经网络分析的作用。该研究项目的总体目标是支持NIMH的使命，促进对精神障碍原因的研究和进展。