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Homeostatic Regulation of Synaptic Function

impaired muscle excitation results in compensatory increase in presynaptic release

Figure Legend. A homeostatic signaling system controls synaptic function at the Drosophila neuromuscular synapse as well as at synapses in the vertebrate peripheral and central nervous systems. In three independent experiments, impaired muscle excitation (red text) revealed the presence of a potent compensatory signaling system that increases presynaptic transmitter release (blue arrows). The compensatory increase in presynaptic release compensates for impaired muscle excitation and allows normal muscle function. This type of homeostatic regulation also occurs in response to the human disease myasthenia gravis where muscle acetylcholine receptors are impaired, demonstrating that this type of signaling is conserved between flies and humans. A variety of other experiments suggest that homeostatic signaling is also a prevalent and potent means to control neural activity in the vertebrate central nervous system

for review see:

Davis and Goodman, 1998, Current Opinion in Neurobiology.
Davis and Bezprozvanny, 2001, Annual Review of Physiology.

 

Project Summary

The precise regulation of neural excitation is essential for proper nerve cell, neural circuit, and nervous system function. During postembryonic development and throughout life, neurons are challenged with perturbations that can alter excitability including changes in cell size, innervation, and synaptic function. The cause of these perturbations can be normal developmental changes associated with our ability to learn and remember, or they can be associated with disease or injury to the nervous system. An increasing number of experiments demonstrate that neurons are able to compensate for these types of perturbation and maintain appropriate levels of excitation. This type of compensation whereby a neuron is able to return to a normal state of excitation is, by definition, homeostasis. The mechanisms of homeostatic compensation within the nervous system are diverse including changes to synapse size, synaptic function, and ion channel function. The implicit importance of homeostasis to the appropriate function of the nervous system suggests that there will be links to neural disease. Ultimately, a thorough understanding of homeostatic signaling in the nervous system at a cellular and molecular level will be required to before we can establish links between impaired homeostasis and diseases of the nervous system. This is a major goal for my laboratory.

We are taking advantage of the powerful genetic tools available in Drosophila to identify genes and signaling pathways that are essential to the homeostatic regulation of synaptic structure and function. These experiments incorporate genetics, synaptic electrophysiology, imaging and molecular studies. To date we have identified a group of approximately 30 genes that may be involved in the mechanisms of homeostasis in the nervous system. We are in the process of characterizing the function of many of these genes. Many of the genes we have identified have clear homologues in the vertebrate genome. Ultimately, we hope to define both the logic of homeostatic regulation in the nervous system and the identity of the underlying signaling systems. Our goal is to pursue the potential cause and cure for neural disease and dysfunction.


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