Disorders in neostriatal dopaminergic and cholinergic signaling underlie a wide variety of psychomotor disorders. One of these disorders- Parkinson's disease (PD)-afflicts roughly 1 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 innervation is a disruption of normal cholinergic functioning. Treatment strategies for PD commonly attempt 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. Our long-term goal is to characterize the molecular and cellular mechanisms of dopaminergic and cholinergic signaling in the neostriatum. The overarching goal of this FIRCA proposal is to further these aims by incorporating patch clamp recording discharge patterning in medium spiny neurons. We will focus on those effects directly attributable to modulation of voltage-dependent Ca2+ channels. Understanding how these channels are modulated by dopamine and acetylcholine has been a major goal of NS 34696. In addition, single cell RT-PCR techniques will be used to phenotype recorded neurons and to provide some insight into the molecular identify of the channels regulating repetitive firing in medium spiny neurons. This FIRCA proposal has two specific aims: 1) To determine the role of L-type Ca2+ channels in the interaction of dopaminergic and muscarinic signaling pathways regulating repetitive discharge identified medium spiny neurons and 2) to determine the role of and P/Q-type Ca2+ channels in the interaction of dopaminergic and muscarinic signaling pathways regulating repetitive discharge in identified medium spiny neurons.
These aims are natural extensions of those outlined in NS34696. By establishing a formal collaboration with Drs. Bargas and Galarraga, we will be able to bring their expertise in current clamp recording in striatal slices to bear on the originally stated research questions. The collaboration will assist in the development of voltage-clamp and single cell RT-PCR approaches in the lab of Drs. Bargas and Galarraga. Also, this collaboration will serve as a means of means of brining these techniques to other neuroscience research programs at UNAM and Mexico City. In so doing, this collaborative award will achieve both the development goals of the Fogarty program and significantly advance the scientific goals of N.I.H.
