METABOTROPIC GLUTAMATE RECEPTORS AND EXCITOTOXICITY

代谢型谷氨酸受体和兴奋性毒性

基本信息

批准号：
7154744
负责人：
FANG ZHENG
金额：
$ 6.89万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7154744
关键词：
ACPD Address Adult Adverse effects Agonist Anxiety Area Attenuated Brain Brain region Calcium Cell Nucleus Cessation of life Chromosome Pairing Condition Cycloleucine Data Development Dicarboxylic Acids Disinhibition Drug Delivery Systems Epilepsy Event Excitatory Synapse Family Fire - disasters Future G-Protein-Coupled Receptors Generations Glutamate Receptor Glutamates Goals Iodides Knowledge Lateral Lateral Septal Nucleus Learning Limbic System Mediating Membrane Potentials Memory Metabotropic Glutamate Receptors Molecular Motor Nature Nerve Degeneration Neuraxis Neurons Neurotransmitters Numbers Parkinson Disease Pathologic Processes Pattern Pertussis Toxin Pharmaceutical Preparations Physiological Polymerase Chain Reaction Property Propidium Propidium Diiodide Psychotic Disorders RNA Interference Rattus Reagent Regulation Research Role Seizures Severities Site Slice Small Interfering RNA Staining method Stains Stroke Structure Symptoms Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Therapeutic alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate drug development excitotoxicity fluoro jade insight member nervous system disorder neurotransmission receptor research study tool

项目摘要

DESCRIPTION (provided by applicant): Glutamate is the most prevalent neurotransmitter in the brain. Metabotropic glutamate receptors (mGluRs) are a family of G-protein coupled receptors that regulate neurotransmission at excitatory synapses in the brain. The diversity and heterogeneous distribution of mGluR subtypes may provide an opportunity for developing drugs to selectively target a specific CNS system and ameliorate symptoms of distinct neurological disorders. However, the role of mGluRs in excitotoxicity remains controversial. The lateral septal nucleus is a major relay nucleus in the limbic system. In lateral septal neurons, mGluR agonists elicit epileptiform burst firing and greatly elevate intracellular free calcium. Preliminary data suggest that this calcium increase results in severe excitotoxicity that is independent of ionotropic glutamate receptors. The goal of this study is to determine the molecular nature of the mGluRs in the lateral septum of rats that mediate the epileptic burst firing and excitotoxicity. In Aiml, a new generation of group selective agonists and antagonists will be tested. Intracellular recordings will be used to study the effects of these drugs on the firing pattern of lateral septal neurons. Excitotoxicity in the slices will be assessed by propidium iodide (PI) loading and fluoro-jade staining. These experiments will determine whether epileptiform burst firing and excitotoxicity are mediated by group I mGluRs alone. In Aim 2, siRNA reagents that target rat mGluRl or mGluRS will be generated and used to functionally silence the expression of mGluRl or mGluRS in organotypic cultures of the rat septum. The effect of selectively reducing mGluRl or mGluRS expression on mGluR-mediated excitotoxicity will then be assessed. By combining pharmacological and RNA-interference approaches, the molecular nature of the mGluRs that mediate the epileptic burst firing and excitotoxicity in lateral septal neurons will be elucidated. The findings will provide critical information for developing drugs that can be used to treat Parkinson's diseases, seizures, psychosis and excitotoxicity associated with stroke.

描述（由申请人提供）：谷氨酸是大脑中最普遍的神经递质。代谢型谷氨酸受体 (mGluR) 是 G 蛋白偶联受体家族，可调节大脑兴奋性突触的神经传递。 mGluR 亚型的多样性和异质性分布可能为开发选择性靶向特定 CNS 系统并改善不同神经系统疾病症状的药物提供机会。然而，mGluRs 在兴奋性毒性中的作用仍然存在争议。外侧间隔核是边缘系统的主要中继核。在外侧间隔神经元中，mGluR 激动剂引起癫痫样爆发并大大提高细胞内游离钙。初步数据表明，钙的增加会导致严重的兴奋性毒性，而这种毒性与离子型谷氨酸受体无关。本研究的目的是确定大鼠外侧隔膜中介导癫痫爆发和兴奋性毒性的 mGluR 的分子性质。在 Aiml 中，将测试新一代的组选择性激动剂和拮抗剂。细胞内记录将用于研究这些药物对外侧间隔神经元放电模式的影响。将通过碘化丙啶（PI）加载和荧光玉染色来评估切片中的兴奋毒性。这些实验将确定癫痫样爆发和兴奋性毒性是否仅由 I 组 mGluR 介导。在目标2中，将产生靶向大鼠mGluR1或mGluRS的siRNA试剂，并用于功能性沉默大鼠隔膜的器官型培养物中mGluR1或mGluRS的表达。然后将评估选择性减少mGluR1或mGluRS表达对mGluR介导的兴奋毒性的影响。通过结合药理学和 RNA 干扰方法，将阐明介导外侧间隔神经元癫痫爆发和兴奋性毒性的 mGluR 的分子性质。这些发现将为开发可用于治疗帕金森病、癫痫发作、精神病和与中风相关的兴奋性中毒的药物提供关键信息。