KNCQ Potassium Channels and Schizophrenia

KNCQ 钾通道和精神分裂症

基本信息

批准号：
8925922
负责人：
MOHAMMADHOSSEIN BEHNAM GHASEMZADEH
金额：
$ 18.51万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925922
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 cognitive task disorder control effective therapy expectation improved information processing novel preclinical study response social therapy development

项目摘要

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.

描述（由申请人提供）：精神分裂症是一种具有毁灭性和破坏性的个人，家庭和社会后果的慢性精神障碍，影响了18岁以上的世界人口约1.1％。在任何一年中，世界上有超过240万美国人和大约5200万人患有与精神分裂症相关的病理（SZ）。 SZ的病因尚未完全了解，其复杂的神经生物学已成为缺乏有效治疗疾病症状的治疗的部分原因。当前的药物和治疗可以改善某些疾病症状；但是，SZ的核心病理（负症状和认知缺陷）不受影响。此外，目前的药物遭受严重的副作用，限制了它们的使用患者。因此，在识别和理解有效治疗SZ的负面和认知症状的大脑机制方面仍然存在至关重要的需求。我们已经确定了脑KCNQ（KV7）电压门控钾通道是能够改善SZ的负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，并且在与SZ功能障碍相关的大脑区域中急切地表达。 KCNQ钾通道具有独特的功能特性，使其成为大脑神经元和网络活动的重要调节剂。我们的初步数据强烈表明，这些通道可以改善SZ动物模型中的行为缺陷。在此提案中，我们试图表征前额叶皮层KCNQ钾通道在与SZ相关的负和认知症状中的作用。此外，我们将使用多站点电生理记录的新技术来研究正常和疾病状态下的大脑网络活动，并确定KCNQ钾通道在调节其活性中的作用。因此，在AIM 1中，KCNQ通道激活剂和阻滞剂的脑外微灌注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（乙酸甲醇，MAM）的发展动物模型来检验我们对KCNQ通道作用的假设。在AIM 2中，我们将使用从海马和自由移动的行为行为的动物进行认知任务的自由移动的动物来表征这两种结构中的网络活动以及在对照和疾病状态下（使用Acute PCP动物模型）中的网络活动来表征自由移动的行为动物的自由移动的动物的自由移动的动物（使用Acute PCP动物模型）的网络活动来表征网络活性的同时多现场电生理记录。此外，我们将监视对KCNQ钾通道调制的网络响应。最后，我们将记录MAM处理的大鼠的海马和前额叶皮层及其对KCNQ钾通道调节的反应。这些研究将提供一个独特的机会，以使用行为，细胞和神经元网络分析来研究重要的大脑信号传导机制KCNQ通道的作用。该研究项目的总体目标是支持NIMH的使命，以促进精神障碍原因的研究和进步。