There is increasing evidence, throughout the nervous system, that homeostatic signaling systems, operating at the level of individual nerve and muscle cells, can interface with the mechanisms of neural plasticity to ensure that neural function remains stable over time. It is further hypothesized that defective homeostatic signaling could contribute to the cause or progression of diverse neurological disease. For example, maladaptive homeostatic signaling is hypothesized to participate in the progression of Alzheimer's Disease and post-traumatic epilepsy while impaired homeostatic signaling could reasonably contribute to other forms of epilepsy/channelopathy. Ultimately, clear links to neurological disease will require a detailed molecular understanding of homeostatic signaling in the nervous system. However, the molecular mechanisms responsible for the homeostatic regulation of neural function remain almost completely unknown. We have previously demonstrated that homeostatic signaling systems modulate neural function in Drosophila. In order to define the molecular mechanisms of homeostatic signaling, we have recently begun a forward genetic screen for mutations that block homeostatic signaling at the Drosophila neuromuscular junction (NMJ). Importantly, this screen uses synaptic electrophysiology as a direct, quantitative measure for altered neurotransmission. This screen has been highly successful. In this grant I present preliminary data for three newly identified genes that we have discovered are essential for synaptic homeostasis. Each of these genes is highly conserved and expressed throughout the vertebrate nervous system. These are among the very first genes to be implicated in the homeostatic modulation of presynaptic transmitter release in any organism. As such, our proposed experiments have the potential to significantly advance our understanding of how stable neural function is normally achieved, and how the stability of neural function becomes compromised during neurological disease.

Public Health Relevance

Throughout the nervous system, there is now evidence that functional properties of neurons are controlled and stabilized by homeostatic signaling mechanisms. It is now widely hypothesized that defective homeostatic signaling could contribute to the cause or progression of diverse neurological diseases such as Alzheimer's Disease and epilepsy. We have recently identified three highly conserved genes that are required for the homeostatic modulation of neurotransmission and are among the very first genes implicated in this fundamental form neural regulation. Therefore, our proposed experiments have the potential to significantly advance our understanding of how stable neural function is normally achieved, and how the stability of neural function becomes compromised during neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039313-11
Application #
7800913
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (03))
Program Officer
Talley, Edmund M
Project Start
2000-02-01
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
11
Fiscal Year
2010
Total Cost
$325,316
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Genç, Özgür; Dickman, Dion K; Ma, Wenpei et al. (2017) MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity. Elife 6:
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Wang, Tingting; Jones, Ryan T; Whippen, Jenna M et al. (2016) ?2?-3 Is Required for Rapid Transsynaptic Homeostatic Signaling. Cell Rep 16:2875-2888
Müller, Martin; Genç, Özgür; Davis, Graeme W (2015) RIM-binding protein links synaptic homeostasis to the stabilization and replenishment of high release probability vesicles. Neuron 85:1056-69
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Parrish, Jay Z; Kim, Charles C; Tang, Lamont et al. (2014) Krüppel mediates the selective rebalancing of ion channel expression. Neuron 82:537-44
Ford, Kevin J; Davis, Graeme W (2014) Archaerhodopsin voltage imaging: synaptic calcium and BK channels stabilize action potential repolarization at the Drosophila neuromuscular junction. J Neurosci 34:14517-25
Davis, Graeme W (2013) Homeostatic signaling and the stabilization of neural function. Neuron 80:718-28
Younger, Meg A; Müller, Martin; Tong, Amy et al. (2013) A presynaptic ENaC channel drives homeostatic plasticity. Neuron 79:1183-96
Müller, Martin; Davis, Graeme W (2012) Transsynaptic control of presynaptic Ca²? influx achieves homeostatic potentiation of neurotransmitter release. Curr Biol 22:1102-8

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