Parkinson's disease (PD), typified by motor dysfunction, is one of the most common neurodegenerative disorders and arises from a degeneration of dopaminergic cells which project to the striatum (Str). In the MPTP model for PD, recordings from the awake monkey have demonstrated that this type of tremor is correlated with rhythmic synchronized burst activity (RSBA) in the subthalamic (STN) and the globus pallidus (GP). Our primary hypothesis is that a recurrent feedback loop between the STN and the GP generates the RSBA in the absence of dopamine. In order to test this hypothesis, we will examine four major points. First, what are the morphological and electrophysiological properties of intrinsically bursting GP and STN cells? Second, is the GP necessary for the generation of RSBA? Third, what is the function of voltage-gated calcium channels and GABAa receptors in the generation of RSBA? Fourth, do dopaminergic inputs affect the generation of RSBA in the STN-GP circuitry? We will employ four different methodological approaches to answer these questions. First, in electrophysiologically and morphologically characterized neurons from GP and STN, we will study the RSBA within and between the STN and the GP using simultaneous intra- and extracellular recording. Second, the contribution of the GP to RSBA in the STN will be studied by comparing two culture systems in which the STN is cultured either with or without the GP using long-term organotypic cultures. Third, the role of calcium channels in intrinsically bursting neurons in the generation of RSBA will be analyzed with whole cell path clamp and calcium imaging methods and the function of GABA receptor subunit compositions with the STN-GP circuitry in the generation of RSBA will be analyzed with immunocytochemistry, in situ hybridization histochemistry, and RT-PCR. Fourth, we will add to the Cx-Str-GP-STN organotypic culture a substantia nigra (SN) culture which provides for the main dopaminergic inputs to the striatum. We will analyze the changes in RSBA as a function of dopamine inputs by manipulating the system acutely and chronically using either dopamine receptor antagonists, or dopamine depletion by 6-hydroxydopamine (6-OHDA). Changes in RSBA will be correlated with changes in rebound burst activity of single cells and/or with changes in the expression of GABAa receptor subunits. This project will provide the basic neuronal frame work regarding the generation of rhythmically synchronized neuronal activity in the basal ganglia that has been related to motor dysfunction in PD.
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