? The precise regulation of neural excitability is essential for proper nerve cell, neural circuit and nervous system function. An increasing body of experimental evidence supports the conclusion that homeostatic signaling mechanisms can modulate synaptic function and contribute to the maintenance of stable neural activity (Marder et al., 1996; Davis and Goodman, 1998; Turrigiano and Nelson, 2000; Davis and Bezprozvanny, 2001; Marder and Prinz, 2003; Turrigiano and Nelson, 2004). We have previously demonstrated the presence of a homeostatic signaling system at the Drosophila NMJ that may require a retrograde signal from muscle to nerve (Davis and Bezprozvanny, 2001). In the human disease myasthenia gravis, and in mouse models of this disease, a similar homeostatic regulation of presynaptic transmitter release is observed (Plompp et al., 1992; Sandrock et al., 1992). To identify the molecular mechanisms of homeostatic signaling we have performed a screen of 1000 gene-specific dsRNA. We identified the Drosophila homologue of the Rho-GEF Ephexin as a gene that, when knocked down, blocks synaptic homeostasis. We have gone on to identify an ephexin loss-of-function mutation, and have confirmed that an ephexin mutation also blocks synaptic homeostasis. In mammalian neurons Ephexin binds to the EphA4 receptor (Shamah et al., 2001). We now show that the Drosophila Eph receptor is a synaptic protein that localizes to the NMJ and we show that dsRNA to the Eph gene also impairs synaptic homeostasis. This proposal is focused on characterizing the role of the Drosophila Eph receptor and ephexin genes during synapse development and synaptic homeostasis. We will address the exciting possibility that the Eph and ephexin genes define the basis of a synaptic signaling cascade that is required for synaptic homeostasis. Although the majority of our experiments focus on Eph-Ephexin signaling, we will also test the involvement of the Ephrin ligand during synaptic homeostasis. We will test whether Ephrin-Eph signaling mediates the retrograde signal that is believed to be involved in synaptic homeostasis at the NMJ. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039313-06
Application #
6949634
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Leblanc, Gabrielle G
Project Start
2000-02-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
6
Fiscal Year
2005
Total Cost
$327,999
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
Orr, Brian O; Fetter, Richard D; Davis, Graeme W (2017) Retrograde semaphorin-plexin signalling drives homeostatic synaptic plasticity. Nature 550:109-113
Orr, Brian O; Gorczyca, David; Younger, Meg A et al. (2017) Composition and Control of a Deg/ENaC Channel during Presynaptic Homeostatic Plasticity. Cell Rep 20:1855-1866
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:
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
Wang, Tingting; Hauswirth, Anna G; Tong, Amy et al. (2014) Endostatin is a trans-synaptic signal for homeostatic synaptic plasticity. Neuron 83:616-29
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

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