REGULATION OF CNS SYNAPTIC TRANSMISSION BY MGLURS

MGLURS 对中枢神经系统突触传递的调节

• 批准号: 6363703
• 负责人: JOEL P GALLAGHER
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363703
• 关键词: NMDA receptors; behavioral habituation /sensitization; brain electrical activity; disease /disorder model; gamma aminobutyrate; glutamate receptor; laboratory rat; neural transmission; neuropharmacology; neuroregulation; phencyclidine; receptor expression; synapses; voltage /patch clamp

DESCRIPTION (Adapted from applicant's abstract): Schizophrenia has been associated with at least two receptor complexes, namely, dopamine and GLU. Theories have been developed which invoke hypotheses supporting specific roles for these neurotransmitters in schizophrenia. The overall goal of this application is to investigate and characterize the cellular pharmacology of presynaptic and postsynaptic mGLURs at pharmacologically and electrically isolated native excitatory and inhibitory synapses, while determining their role in an animal model of the GLU-NMDA Receptor Hypofunction (NRF)-hypothesis of schizophrenia. Intracellular recordings from a brain slice preparation of the dorsolateral septal nucleus (DLSN) will be used to investigate the cellular actions of specific mGLUR agonists and antagonists for the three GROUPs of mGLURs (I, II, III). The specific aims of this application will determine: (1) the mechanisms by which an endogenous excitatory transmitter, GLU, regulates its own release via specific presynaptic mGLURs (autoreceptors); (2) how activation of mGLURs on gamma-aminobutyric acid (GABA)ergic terminals regulates the release of GABA via other types of presynaptic mGLURs (heteroreceptors); and (3) how activation of a postsynaptic mGLUR may potentiate the NMDA component of an excitatory synaptic terminal, a component suggested to be depressed in the NRF hypothesis of schizophrenia. Finally, mGLUR mechanisms in control animals will be compared with brains of animal models of schizophrenia from rats treated chronically with PCP, a drug known to induce behavioral changes similar to those seen in patients with schizophrenia. The DLSN slice preparation has been chosen to study since DLSN contains the relevant neuronal circuitry implicated in the GLU-NRF-hypothesis of schizophrenia as proposed by Coyle (Fig. 3) and the DLSN expresses multiple types of mGLURs. Furthermore, no comparable circuitry is available in a more reduced preparation. These experiments will enhance our understanding of the mechanisms of normal synaptic transmission and transmission in an animal model of schizophrenia. Together these data may provide evidence for the use of a novel group of drugs in the treatment of schizophrenia.

描述(改编自申请者摘要)：精神分裂症 与至少两个受体复合体相关，即多巴胺和GLU。 已经发展出一些理论，这些理论援引支持特定理论的假设 这些神经递质在精神分裂症中的作用。的总目标是 这个应用程序是为了研究和表征细胞 突触前和突触后mGluRs的药理学和 电隔离的天然兴奋性和抑制性突触，而 确定它们在GLU-NMDA受体动物模型中的作用 功能减退(NRF)-精神分裂症的假说。细胞内记录 取自背外侧隔核(DLSN)的脑片 将用于研究特定mGluR激动剂的细胞作用 和mGluR三组(I、II、III)的拮抗剂。具体的 本申请的目的将决定：(1) 内源性兴奋性递质GLU通过 特异性突触前mGluR(自身受体)；(2)mGluRs如何激活 γ-氨基丁酸(GABA)能终末调节GABA的释放 通过其他类型的突触前mGluR(异型受体)；以及(3)如何 突触后mGluR的激活可能增强NMDA成分 兴奋性突触终末，一个被认为是被抑制的成分 精神分裂症的NRF假说。最后，mGluR机制在控制中 动物将与精神分裂症动物模型的大脑进行比较 长期使用五氯苯酚治疗的大鼠，这是一种已知会导致行为变化的药物 类似于精神分裂症患者的症状。DLSN切片 选择制剂进行研究，因为DLSN含有相关的 精神分裂症AS的GLU-NRF假说涉及的神经元回路 由Coyle提出(图3)。3)DLSN表达多种类型的mGluR。 此外，没有类似的电路可用于更精简的 准备工作。这些实验将加深我们对 动物正常突触传递和传递的机制 精神分裂症的典范。这些数据加在一起可能会为 一组新药在精神分裂症治疗中的应用。