) 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. Despite the explosion of information on the pharmacology of acetylcholine in the neostriatum, physiological information has been difficult to obtain due to the relative rarity of cholinergic interneurons compared with the spiny projection cells. Using infrared differential interference contrast microscopy, we have recorded from identified cholinergic neurons in slices, and shown that they are intrinsic pacemakers that fire in three distinctly different spontaneous firing modes in the absence of synaptic input. 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 cell recording of identified cholinergic interneurons in slices to determine: (1) the ionic conductances that give rise to the three spontaneous firing modes, (2) the way in which the spontaneous firing is controlled and disrupted by afferent and intrinsic synaptic input to the cholinergic cells, and (3) the dynamics of intracellular calcium which we hypothesize acts as a critical intermediary in the synaptic control of cholinergic cell activity. Calcium imaging using intracellular filling with the indicator fura-2 will be used to directly examine the ongoing cyclic fluctuations in intracellular calcium level, the spatial distribution of calcium transients within the cell, and the interaction between synaptic inputs and intracellular calcium dynamics that sculpts the firing pattern. Following physiological recordings, neurons loaded with biocytin will be prepared for subsequent anatomical analyses and these data will be combined and used in computer simulations to investigate the dynamic interaction between synaptic inputs and intrinsic properties in the generation of natural firing patterns.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037760-05
Application #
6393966
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Sheehy, Paul A
Project Start
1998-08-25
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2001
Total Cost
$133,282
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Beatty, Joseph A; Sullivan, Matthew A; Morikawa, Hitoshi et al. (2012) Complex autonomous firing patterns of striatal low-threshold spike interneurons. J Neurophysiol 108:771-81
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
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
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
Bennett, B D; Wilson, C J (1999) Spontaneous activity of neostriatal cholinergic interneurons in vitro. J Neurosci 19:5586-96
Bennett, B D; Wilson, C J (1998) Synaptic regulation of action potential timing in neostriatal cholinergic interneurons. J Neurosci 18:8539-49