Synaptic homeostasis is a protective mechanism employed by neurons to counterbalance changes in global neural activity. The last decade has seen intensive study in this field for glutamatergic synapses, however, almost nothing is known about whether synaptic homeostasis is also mediated by other excitatory receptors, such as nicotinic acetylcholine receptors (nAChRs). Indeed, cholinergic synaptic homeostasis has been implicated in important pathological conditions, such as Alzheimer's disease (AD) and nicotine dependence. In this R21 application, our goal is to validate a new system for studying cholinergic synaptic homeostasis and break new ground in an important area that has not yet been explored. The Drosophila CNS provides an ideal model for studying cholinergic synaptic homeostasis since nAChRs are the major excitatory receptor in Drosophila central neurons. Since mammalian ?7 nAChRs are among the most abundant and widespread of nAChRs, and have been implicated in Alzheimer's disease, nicotine addiction, nicotine-induced seizures, and schizophrenia, we focus on the Drosophila ?7 like receptor (D?7) to validate our model. Using primary neuronal cultures in parallel with a cultured brain preparation, we propose to manipulate neural activity, and assay for changes in synaptic strength and changes in nAChR localization and distribution. We will also test the physiological relevance of cholinergic synaptic homeostasis by examining effects on a known behavioral output mediated by D?7 nAChRs, the giant fiber mediated escape behavior. The development of this novel system, which involves the combination of primary cultures, an ex-vivo brain preparation, and a quantifiable behavioral output, will be unique to the field and allow us to answer long-awaited questions about cholinergic synaptic homeostasis.

Public Health Relevance

Although nearly everything we know about synaptic homeostasis has come from studies on glutamate receptors, there is significant evidence that cholinergic synaptic homeostasis, mediated by nicotinic acetylcholine receptors (nAChRs), may underlie key events in important pathological conditions. For example, in Alzheimer's disease (AD), changes in nAChRs have been suggested to arise as a homeostatic response to synaptic loss and depression that occurs during early stages of the disease. While this provides initial protection from a faster decline in cognitive function, this homeostatic response has also been suggested to contribute to the progression of neurodegeneration that ensues with AD. Prolonged nicotine exposure also results in an increase in nAChRs that has been suggested to be a homeostatic response to the desensitization of nAChRs induced by nicotine activation. Understanding how nAChR-mediated homeostasis is induced, signaled, and manifested, will give important insight into new avenues of treatment for these devastating conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Stewart, Randall R
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Colorado State University-Fort Collins
Veterinary Sciences
Schools of Veterinary Medicine
Fort Collins
United States
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