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.
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