The primary pathophysiological change giving rise to Parkinson's disease (PD) is the death of substantia nigra dopaminergic neurons. Based on this, Levodopa (L-DOPA), the immediate precursor of dopamine, remains the most effective drug for treating motor manifestations of PD. However, while effective early in treatment, the chronic use of L-DOPA leads to side effects that often limit therapy. It is well established that a major pathophysiological change giving rise to the symptoms of PD is an increase of basal ganglia outflow to thalamocortical neurons due to excessive excitatory glutamatergic drive from the subthalamic nucleus (STN). Therefore, any pharmacological manipulation that reduces the net output of the STN would be expected to have a therapeutic effect in the treatment of PD. Thus far, major focus to reduce transmission at STN synapses has been on the use of ionotropic glutamate receptor (iGluRs) antagonists. However, the long-term therapeutic efficacy of such treatment is limited by serious side effects because iGluRs mediate fast excitatory transmission at the majority of glutamateric synapses in the central nervous system. Recently, it has become clear that glutamate also activates receptors coupled to effector systems through GTP-binding proteins. These receptors, referred to as metabotropic glutamate receptors (mGluRs), are widely distributed throughout the central nervous system where they play important roles in regulating cell excitability and synaptic transmission. The distribution of mGluRs in the basal ganglia suggest that members of this receptor family could serve as targets for novel therapeutic agents that would be effective in the treatment of PD. However, the precise roles of mGluRs in the basal ganglia are not known. The goal of this project is to test the hypothesis that specific mGluR subtypes play a therapeutically relevant role in regulating basal ganglia function. This will be achieved by combining high resolution anatomical techniques at the light and electron microscopic level using mGluRs subtype specific antibodies and anterograde tract-tracing methods with in vitro electrophysiological and pharmacological techniques.
Three specific aims will be addressed: (1) Test the hypothesis that group II mGluRs serve as presynaptic receptors involved in reducing glutamate release from STN terminals in the basal ganglial output nuclei. (2) Test the hypothesis that postsynaptically group I mGluRs are involved in regulating excitability in target nuclei of the STN and (3) Test the hypothesis that group III mGluRs serve as a presynaptic heteroreceptor involved in reducing GABA release from terminals of striatal projections to the external globus pallidus (GPe). These studies will provide new insights into the role of mGluRs is regulating basal ganglia function, and help developing novel therapeutic strategies to the treatment of PD.
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