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Nicotinic receptors & synaptic aging

Institution: University of California, San Diego
Investigator(s): Jay Coggan, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10KT-0082 Award: $224,973
Subject Area: Nicotine Dependence
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
The smoking of cigarettes is well known to be ruinous to general human health. Smoking behavior in the general public is difficult to curtail owing to the highly addictive quality of nicotine, a bioactive component of tobacco. Paradoxically, tobacco smoking is often reported to aid in delaying or relieving some of the symptoms of nervous system dysfunction such as schizophrenia, Parkinson's disease, and Alzheimer's disease. The process of aging in the mammalian nervous system results in a wide variety of changes at the cellular and molecular level that compromise function at the level of cognition and behavior. One of the most global and profound changes is a reduction in the number of specific proteins on the surface of the cells that act as receptors for nicotine. These neuronal nicotinic receptors (nAChR) are located at synapses - the specialized sights of information transfer from one nerve cell to another. The loss of nAChRs is thought to be involved in devastating illnesses including Alzheimer's disease, Parkinson's disease, Lewy bodies, and general cognitive decline associated with aging. Additional ailments that are not strictly related to aging but which also involve nAChRs and perhaps similar molecular mechanisms associated with nAChRs and synaptic dysfunction include schizophrenia, epilepsy, Tourette’s syndrome, and neuronal death.

In order to understand normal and pathological biological functions in humans, researchers must make use of animal models that simulate as closely as possible the human phenomena. A mouse model of synaptic aging and nAChR loss has been developed that provides an accessible and relatively simple neural system for study. This model involves use of ganglia, sometimes referred to as miniature brains, which are small groups of nerve cells located throughout the body that relay and process information outside of the brain and spinal chord. The experiments proposed herein are aimed at understanding the fundamental events involved in the dysfunction and eventual elimination of a nAChR-type synapse including: reductions in nAChR density, impaired ability of the presynaptic nerve cell to communicate with the postsynaptic cell, the potential breakdown of cellular structures related to the synapse, and complete loss of innervation. In addition, experiments will be carried out to test the effects of chronic nicotine administration on the fate of nAChRs and overall synaptic efficacy.

The aims of this proposal are designed to lay a foundation of knowledge about a model nAChR-type synapse and the mechanisms of its elimination. The culmination of this proposal addresses the issue of avoiding nicotine and tobacco exposure. The long term goal is to determine the specific events involved in nAChR loss with age and design specific, non-addictive drugs, that could replace the use of tobacco as a source of nAChR stimulation, thus preventing further public health costs as the nation's population ages.
Publications

PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons.
Periodical: Neuron Index Medicus:
Authors: Conroy W, Liu Z, Nai Q, Coggan J, Berg D ART
Yr: 0 Vol: Nbr: Abs: Pg:

Age-associated synapse elimination in mouse parasympathetic ganglia.
Periodical: Journal of Neurobiology Index Medicus:
Authors: Coggan JS, Grutzendler J, Bishop DL, Cook MR, Gan W, Heym J, Lichtman JW ART
Yr: 2004 Vol: 60 Nbr: Abs: Pg: 214-226