The precise execution of complex movements results from the convergence of direct input from primary afferent neurons and corticospinal projections onto motoneurons, as well as indirect inputs from spinal cord interneurons. Presynaptic modulation of synaptic transmission is an important component of this circuitry. Preliminary studies in the hemisected spinal cord indicate that presynaptic nicotinic acetylcholine receptors (nAChRs) enhance excitatory synaptic inputs to spinal motoneurons. The goal of this proposal is to examine the biophysical mechanisms and receptor components that underlie nAChR-mediated enhancement of synaptic transmission in the spinal cord. The primary assay of presynaptic nAChRs will assess changes in the spontaneous and evoked synaptic transmission in recordings from motoneurons. In initial studies, the modulation of synaptic transmission by nAChRs will be examined in two semi-intact preparations, transverse slices and hemisected spinal cord, under conditions that closely mimic the native environment. Characterization of the effects of nAChR activation on evoked transmission will enable identification of the class(es) of afferent inputs that express these receptors. These findings will then guide the making of cultures of dissociated motoneurons that are innervated by explants of the appropriate afferent inputs. Using these cocultures, more detailed molecular, pharmacological and biophysical analyses will be made of the presynaptic nAChRs that modulate each type of afferent inputs to motoneurons. This proposal will also examine the influence of endogenously released ACh on presynaptic nAChRs and synaptic efficacy. Endogenous activation of presynaptic nAChRs will be achieved by stimulating the motoneuron under study to evoke a local release of ACh. Finally, the effects of inhibitors of acetylcholine esterase, the enzyme that is responsible for eliminating ACh after its release, will also be examined. Collectively, these studies will provide a detailed pharmacological, molecular, and biophysical analysis of the receptor subtypes involved in nAChR-mediated presynaptic enhancement of excitatory transmission in the spinal cord. These studies will significantly advance our understanding of the factors that influence motoneuron excitability and hopefully identify new approaches to alleviating the debilitating symptoms associated with degenerative diseases of motor and sensory neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS035090-01A1
Application #
2408326
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Baughman, Robert W
Project Start
1997-08-25
Project End
2000-05-31
Budget Start
1997-08-25
Budget End
1998-05-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Mansvelder, Huibert D; Fagen, Zara M; Chang, Ben et al. (2007) Bupropion inhibits the cellular effects of nicotine in the ventral tegmental area. Biochem Pharmacol 74:1283-91
Genzen, Jonathan R; McGehee, Daniel S (2005) Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn. Brain Res 1031:229-37
Genzen, Jonathan R; McGehee, Daniel S (2003) Short- and long-term enhancement of excitatory transmission in the spinal cord dorsal horn by nicotinic acetylcholine receptors. Proc Natl Acad Sci U S A 100:6807-12
Fagen, Zara M; Mansvelder, Huibert D; Keath, J Russel et al. (2003) Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine. Ann N Y Acad Sci 1003:185-95
Mansvelder, Huibert D; Keath, J Russel; McGehee, Daniel S (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33:905-19
Genzen, J R; Van Cleve, W; McGehee, D S (2001) Dorsal root ganglion neurons express multiple nicotinic acetylcholine receptor subtypes. J Neurophysiol 86:1773-82
Mansvelder, H D; McGehee, D S (2000) Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27:349-57
Devay, P; McGehee, D S; Yu, C R et al. (1999) Target-specific control of nicotinic receptor expression at developing interneuronal synapses in chick. Nat Neurosci 2:528-34
McGehee, D S (1999) Molecular diversity of neuronal nicotinic acetylcholine receptors. Ann N Y Acad Sci 868:565-77