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 #
5R01NS039313-13
Application #
8269087
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
2012-05-01
Budget End
2013-04-30
Support Year
13
Fiscal Year
2012
Total Cost
$322,029
Indirect Cost
$107,654
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
Parrish, Jay Z; Kim, Charles C; Tang, Lamont et al. (2014) Kr├╝ppel mediates the selective rebalancing of ion channel expression. Neuron 82:537-44
Wang, Tingting; Hauswirth, Anna G; Tong, Amy et al. (2014) Endostatin is a trans-synaptic signal for homeostatic synaptic plasticity. Neuron 83:616-29
Younger, Meg A; Muller, Martin; Tong, Amy et al. (2013) A presynaptic ENaC channel drives homeostatic plasticity. Neuron 79:1183-96
Davis, Graeme W (2013) Homeostatic signaling and the stabilization of neural function. Neuron 80:718-28
Muller, Martin; Pym, Edward C G; Tong, Amy et al. (2011) Rab3-GAP controls the progression of synaptic homeostasis at a late stage of vesicle release. Neuron 69:749-62
Marie, Bruno; Pym, Edward; Bergquist, Sharon et al. (2010) Synaptic homeostasis is consolidated by the cell fate gene gooseberry, a Drosophila pax3/7 homolog. J Neurosci 30:8071-82
Bergquist, Sharon; Dickman, Dion K; Davis, Graeme W (2010) A hierarchy of cell intrinsic and target-derived homeostatic signaling. Neuron 66:220-34
Frank, C Andrew; Pielage, Jan; Davis, Graeme W (2009) A presynaptic homeostatic signaling system composed of the Eph receptor, ephexin, Cdc42, and CaV2.1 calcium channels. Neuron 61:556-69
Dickman, Dion K; Davis, Graeme W (2009) The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science 326:1127-30
Heerssen, Heather; Fetter, Richard D; Davis, Graeme W (2008) Clathrin dependence of synaptic-vesicle formation at the Drosophila neuromuscular junction. Curr Biol 18:401-9

Showing the most recent 10 out of 17 publications