Altered function of the neostriatal cholinergic interneurons has been implicated in the pathology of Parkinson's disease, Huntington's disease, and a variety of other disorders. The observation that cholinergic antagonists are clinically effective in treating Parkinson's disease has led many investigators to suggest that within the striatum there is a balance of opposing actions of dopamine and acetylcholine. Despite the explosion of information on the pharmacology of acetylcholine in the neostriatum, physiological information has been difficult to obtain due to the rarity of cholinergic interneurons compared to the other cells in the striatum. Using infrared differential interference contrast microscopy, we have recorded from identified cholinergic neurons in slices, and have shown that they are intrinsic pacemakers that exhibit three distinctly different spontaneous filing patterns, even in the absence of fast synaptic input (but with neuromodulators intact). One of the firing patterns resembles that seen in experimental Parkinsonism. This finding provides a window on several otherwise inexplicable observations, including the rhythmic synchronous activity of these neurons in monkeys rendered Parkinsonian by experimental treatment with MPTP. In the proposed experiments, we will employ whole ceil recording of identified cholinergic interneurons and calcium imaging in single cells to determine (1) The ionic mechanisms of the rhythmic bursting firing mode, which most resembles that seen in Parkinsonism, which we already know is related to modulation of calcium and calcium dependent ion channels (2) The basis for synchronization of cholinergic interneurons when they are firing in the bursting mode, including the synaptic connectivity among cholinergic cells and (3) The influence of D1 and D2 dopaminergic agonists and antagonists on the firing patterns of cholinergic interneurons. The effects of dopamine on firing pattern will be directly related to other studies on dopaminergic modulation of specific ion channels to provide an integrated understanding of the actions of dopamine on cholinergic interneurons and the neostriatal circuitry.
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