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Cell adhesion at nicotinic synapses

Institution: University of California, San Diego
Investigator(s): Gallen Triana-Balzer, BA
Award Cycle: 2005 (Cycle 14) Grant #: 14DT-0092 Award: $59,454
Subject Area: Nicotine Dependence
Award Type: Dissertation Awards
Abstracts

Initial Award Abstract
Tobacco use is the leading preventable cause of death in the United States. Nicotine is the primary component in tobacco responsible for the addiction. The molecular mechanism of nicotine addiction remains poorly understood, but it is clear that the addiction must be mediated by naturally occurring nicotinic acetylcholine receptors (nAChRs) responsive to the compound. These receptors are widely distributed in the brain and normally are activated by the endogenous neurotransmitter acetylcholine. The nicotinic signaling, so-called, influences many aspects of brain function including memory and learning, and attention and motivation. During embryogenesis and early postnatal life, nicotinic signaling appears to play an important role in shaping the developing circuits. The receptors are also activated by exogenous nicotine (hence the receptor name). Little is known about how these developmental processes are affected by chronic exposure to low doses of nicotine such as those likely to be encountered indirectly through maternal usage of tobacco. A key component to understanding these phenomena is knowledge of how nicotinic synapses are formed and how those events are impacted by inappropriate exposure to nicotine.

This predoctoral research proposal will examine the cell adhesion molecule L1 as being an important constituent of developing nicotinic synapses. Preliminary results suggest that L1 can be located both pre- and postsynaptically at interneuronal nicotinic synapses early in development. Moreover, L1 appears to act from both locations to induce and stabilize presynaptic components over the corresponding postsynaptic specialization. This proposal will replicate these preliminary results and extend them to understand the significance of L1 in nicotinic synapse formation. Three specific aims are proposed. The first aim will test the hypothesis that L1 acts from postsynaptic locations to organize presynaptic components at nicotinic interneuronal synapses. The second will test the hypothesis that L1 also acts from presynaptic sites to coordinate synaptic assembly. These studies will be carried out both on interneuronal and nerve-muscle nicotinic synapses. The third and final aim will examine L1 effects in motor pathways in vivo, focussing on the neuromuscular junction. Each of the aims will utilize immunostaining for pre- and postsynaptic components to visualize the developing synapse. In some case, dye uptake will be used to assess functionality of the synaptic contacts. L1 contributions will be manipulated by transfecting cells in culture with wildtype and dominant negative constructs. The constructs will be introduced in vivo by electroporation.

These studies are expected to provide fundamental new insights into the role of cell adhesion molecules in determining synaptic structure. Specifically they will indicate the extent to which L1 guides nicotinic synapse formation on neurons and muscle. This information will be valuable for understanding basic developmental events in the nervous system and will also have biomedical relevance. By discovering the components key for establishing normal nicotinic signaling, it may be possible either to manipulate or protect them in ways that compensate for toxic exposure to nicotine during embryogenesis and early postnatal life.
Publications

Pre- and postsynaptic actions of L1-CAM in nicotinic pathways
Periodical: Neuroscience Index Medicus:
Authors: Gallen B. Triana-Baltzer, Zhaoping Liu, and Darwin K. Berg ART
Yr: 2006 Vol: 33 Nbr: Abs: Pg: 214-226