The subthalamic nucleus (STN) is a member of the basal ganglia that is recognized as playing a pivotal role in the expression of symptoms of Parkinson's disease and in the generation of dyskinesia that is caused by dopaminergic treatment of Parkinson's disease. Also, deep brain stimulation (DBS) of the STN is now recognized as an effective treatment of Parkinson's disease, and yet the mechanism of action remains in doubt. In general, little is known about physiological and pharmacological mechanisms that regulate the activity of STN neurons. We propose to use standard whole-cell recording techniques to characterize the pharmacology of neurotransmission and effects of high-frequency electrical stimulation (HFS) on STN neurons in the rat brain slice. Bipolar electrodes placed in the slice will evoke excitatory and inhibitory synaptic currents in STN neurons. In order to characterize changes in membrane properties that are produced by chronic dopamine depletion, recordings will be done in STN from rats treated unilaterally with 6- OHDA, and compared with those obtained in control STN. Long-term changes in inhibitory synaptic transmission caused by HFS of the STN may provide a model mechanism to explain the efficacy of DBS in the treatment of human Parkinson's disease. Experiments designed to define the physiological actions and receptor pharmacology of serotonin in the STN should help define the role of this important modulator of synaptic transmission. Investigations to uncover mechanisms underlying glutamate receptor-mediated burst firing should help define ionic currents that regulate STN neuronal excitability. Finally, we plan to define interactions between metabotropic glutamate and N-methyI-D-aspartate receptors in normal and dopamine depleted tissue. In addition to providing new information on the role of the STN in Parkinson's disease, results from these studies should also be relevant to the greater field of movement disorders. ? ?
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