MGLUR4 AS THERAPEUTIC TARGET IN PARKINSON?S DISEASE

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这三组mGluRs在基底神经节中的突触前和突触后位点强烈表达。Smith博士实验室与范德比尔特大学的Conn博士合作进行的啮齿动物研究提供了明确的证据，表明第III组mGluR亚型mGluR 4是帕金森病非多巴胺能治疗的一个非常有前途的靶点。通过使用电子显微镜程序和体外切片电生理学，Smith博士及其同事已经表明，mGluR 4位于突触前，位于基底神经节回路中的两个关键突触处，这些突触在帕金森病中变得过度活跃，即皮质纹状体神经元突触和纹状体苍白球GABA能突触。大鼠脑切片的电生理学研究表明，III组mGluRs的激活减少了这些突触的突触传递，并且在帕金森病大鼠模型中脑内注射III组激动剂提供了抗帕金森病益处。基于这一坚实且极具前景的基础，Smith博士实验室正在进行的研究旨在测试在MPTP治疗的非人灵长类帕金森病模型中脑内给予III组mGluR激动剂和mGluR 4变构增效剂（在Conn博士实验室制备）的抗帕金森病疗效。此外，为了更好地了解这些化合物在灵长类动物中的行为抗帕金森病益处的潜在可能机制，记录了苍白球神经元对mGluR 4激动剂和增效剂给药的生理活性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The three groups of mGluRs are strongly expressed at pre- and post-synaptic sites in the basal ganglia. Rodent studies achieved in Dr Smith laboratory in collaboration with Dr Conn at Vanderbilt University have provided clear evidence that the group III mGluR subtype, mGluR4, represents a highly promising target for non-dopaminergic therapy in Parkinson's disease. Through the use of electron microscopy procedures and in vitro slice electrophysiology, Dr Smith and colleagues have shown that the mGluR4 is located pre-synaptically at two key synapses in the basal ganglia circuits that become overactive in Parkinson's disease, namely the corticostriatal glutamatergic synapse and the striatopallidal GABAergic synapse. Electrophysiological studies in rat brain slices indicate that activation of group III mGluRs reduces synaptic transmission at these synapses and that intracerebral injections of group III agonists provide antiparkinsonian benefits in rat models of Parkinson's disease. Based on this solid and highly promising foundation, ongoing studies in Dr Smith laboratoryl aim at testing the antiparkinsonian efficacy of intrecerebral administration of group III mGluR agonist and mGluR4 allosteric potentiator (prepared in Dr Conn's laboratory) in the MPTP-treated nonhuman primate model of Parkinson's disease. Furthermore, in order to better understand the possible mechanisms underlying the behavioral antiparkinsonian benefits of these compounds in primates, the physiological activity of pallidal neurons is being recorded in response to the administration of mGluR4 agonists and potentiators.