Disorders in neostriatal dopaminergic and cholinergic signaling underlie a wide variety of psychomotor disorders. One of these disorders - Parkinson's disease (PD) - afflicts roughly one in every 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have made it clear that PD results from the degeneration of nigrostriatal dopaminergic neurons. Accompanying the loss of the dopaminergic innervations is a disruption of normal cholinergic functioning. Treatment for PD commonly attempts to elevate neostriatal dopamine and depress cholinergic signaling to help re-establish a balance between these systems. In spite of the profound importance of neostriatal dopamine (DA) and acetylcholine (ACH) to this disease process, relatively little is known about how these neuromodulators control cellular excitability and function. The long-term goal is to characterize the molecular and cellular mechanisms of dopaminergic and cholinergic signaling in the neostriatum. This proposal will focus on characterizing how these transmitters modulate voltage-dependent Ca2+ currents within functionally and anatomically defined populations of neostriatal neurons. The investigators propose to achieve their immediate aims by combining three powerful experimental approaches. The impact of postsynaptic dopaminergic and cholinergic signaling pathways on the biophysical properties of voltage-dependent Ca2+ currents will be studied using patch-clamp analyses of acutely-isolated and cultured neostriatal neurons identified by retrograde labeling and mRNA profiling. In biophysically characterized neurons, the molecular identity of the signaling elements used by DA and ACH will be determined using pharmacological, fluorometric and single cell mRNA profiling methods. Cellular profiles or fingerprints will be constructed by screening for specific mRNAs, including those coding for DA and ACH receptors, signaling enzymes, transmitters and targeted ion channels. These tools will be used to achieve three specific aims: 1) to characterize the postsynaptic mechanisms mediating dopaminergic modulation of voltage-dependent Ca2+ channels within defined neostriatal phenotypes; 2) to characterize the postsynaptic mechanisms mediating cholinergic modulation of voltage-dependent Ca2+ channels within these same cell types; 3) to determine how dopaminergic and cholinergic pathways interact at the cellular level. By combining anatomical, physiological and molecular analyses at the single cell level, the investigators should be able to provide detailed information about the molecular and cellular mechanisms mediating dopaminergic and cholinergic signaling in functionally relevant subsets of neostriatal neurons. The insights gained from this work should provide a cellular framework in which the behavior of large collections of neurons and the neostriatum itself can be understood. In so doing, it should open the door to the development of novel and powerful therapeutic strategies not only for Parkinson's disease but other disorders with neostriatal determinants such as schizophrenia.
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