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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS037760-12
Application #
7752516
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Sutherland, Margaret L
Project Start
1998-08-25
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
12
Fiscal Year
2010
Total Cost
$306,050
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
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Sciamanna, Giuseppe; Wilson, Charles J (2011) The ionic mechanism of gamma resonance in rat striatal fast-spiking neurons. J Neurophysiol 106:2936-49
Goldberg, Joshua A; Teagarden, Mark A; Foehring, Robert C et al. (2009) Nonequilibrium calcium dynamics regulate the autonomous firing pattern of rat striatal cholinergic interneurons. J Neurosci 29:8396-407
Tepper, James M; Wilson, Charles J; Koos, Tibor (2008) Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons. Brain Res Rev 58:272-81
Wilson, Charles (2008) Up and down states. Scholarpedia J 3:1410
Ding, Jun; Guzman, Jaime N; Tkatch, Tatiana et al. (2006) RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion. Nat Neurosci 9:832-42
Wilson, Charles J; Goldberg, Joshua A (2006) Origin of the slow afterhyperpolarization and slow rhythmic bursting in striatal cholinergic interneurons. J Neurophysiol 95:196-204
Goldberg, Joshua A; Wilson, Charles J (2005) Control of spontaneous firing patterns by the selective coupling of calcium currents to calcium-activated potassium currents in striatal cholinergic interneurons. J Neurosci 25:10230-8
Wilson, Charles J (2005) The mechanism of intrinsic amplification of hyperpolarizations and spontaneous bursting in striatal cholinergic interneurons. Neuron 45:575-85
Bennett, B D; Callaway, J C; Wilson, C J (2000) Intrinsic membrane properties underlying spontaneous tonic firing in neostriatal cholinergic interneurons. J Neurosci 20:8493-503

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