Cholinergic signaling mediated by ionotropic (nicotinic) acetylcholine receptors (iAChRs) plays key roles in the mammalian nervous system. iAChRs modulate neurotransmitter release at diverse synapse types across virtually every area of the brain and spinal cord, and in addition, regulate the activity of inhibitory interneurons in critical brain areas. Alterations in iAChR signaling are associated with a number of debilitating neurological disorders including Alzheimer's disease, schizophrenia and certain forms of epilepsy. Moreover, nicotine binding to nicotinic receptors in the nervous system initiates the cellular and molecular cascade that results in nicotine addiction. Despite the clear importance of iAChR signaling in normal brain physiology and health, there are major gaps in our understanding of the cellular mechanisms that regulate cholinergic signaling in the brain. We have made the exciting observation that iAChRs also regulate inhibitory neuron activity in the genetically tractable model organism Caenorhabditis elegans. We have developed a powerful system to study the trafficking, localization and function of these receptors in the dendrites of inhibitory neurons located in a simple 3-layer circuit that controls C. elegans movement. This proposal aims to use the genetic tools we have generated for manipulation of activity levels in this circuit, along with the powerful array of molecular genetic approaches available in C. elegans, to explore fundamental questions in iAChR biology. In this project we will (Aim 1) characterize iAChR subcellular localization, subunit composition, in vivo dynamics, and molecular pathways responsible for delivery of iAChRs to specific subcellular domains on inhibitory neurons;
(Aim 2) investigate how altered cholinergic innervation of GABA neurons leads to defects in the development or maintenance of GABA synapses;
(Aim 3) determine the role of a novel neurexin signaling pathway in shaping GABA synapse development. We expect that our studies of this experimentally tractable circuit in the worm will provide exciting new insights into mechanisms for biological regulation of iAChRs in the brain, and their important roles in regulating inhibitory signaling. Additionally, the identification and functional characterization of conserved genetic pathways that regulate synapse formation and function in our experiments will ultimately yield novel drug targets for therapeutic strategies designed to treat neurological disorders involving cholinergic signaling.

Public Health Relevance

The neurotransmitter acetylcholine plays conserved roles in mediating communication between neurons from nematodes to humans. Alterations in acetylcholine-mediated signaling are a hallmark of a wide variety of degenerative neurological disorders and nicotine addiction, yet we know very little about the molecular pathways that regulate this process in the mature nervous system or about how deficits alter connectivity in the developing nervous sytem. Our work will provide fundamental knowledge about mechanisms for regulation of acetylcholine-mediated signaling and is expected to provide critical insights into how defects in acetylcholine- mediated signaling cause disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Stewart, Randall R
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University of Massachusetts Medical School Worcester
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United States
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