Metabotropic glutamate receptor-mediated synaptic plasticity in the basal ganglia

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PROJECT SUMMARY The basal ganglia play a critical role in controlling voluntary movement and motor learning. Disruption of basal ganglia function causes devastating movement disorders such as Parkinson's disease (PD). In order to discover novel treatments for disorders such as PD, intense effort has been focused on understanding transmission in the basal ganglia in both normal and pathological states (DeLong and Wichmann, 2007). Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the basal ganglia and modulate synaptic transmission at every major synapse within the basal ganglia motor circuit (Conn et al., 2005). Understanding the function of mGluRs in the basal ganglia in normal and disease states has led to identification of several mGluR subtypes that may provide promising targets for pharmacological treatment of PD. We are particularly interested in the role of group II mGluRs (mGluR2 and mGluR3) at the synapse between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). The STN-SNr synapse is an excitatory synapse that plays a key role in regulating information output from the basal ganglia and is overactive in PD patients. Group II mGluRs regulate both acute and long- term depression (LTD) of excitatory transmission at the STN-SNr synapse (Bradley et al. 2000; Wittmann et al. 2002). For the proposed studies, I will use whole-cell electrophysiological techniques to measure excitatory postsynaptic currents from GABAergic SNr neurons in acute brain slices. First, I will use subtype-selective pharmacological tools that we have recently developed and mGluR2 and -3 knockout mice to determine which group II mGluR subtype(s) mediates acute and long-term effects of group II mGluR agonists on excitatory transmission. In addition, I will characterize the synaptic events involved in the induction of LTD in order to gain an increased understanding of the mechanisms underlying this novel form of synaptic plasticity. Finally, I will test the effect of dopamine depletion in order to understand how mGluR function might be altered in pathological states such as PD. Understanding how dopamine modulates mGluR function is important for the therapeutic potential of drugs targeting mGluRs for treating PD, as well as how changes in mGluR function may contribute to the pathogenesis of PD symptoms.