The causes and progression of several neurological diseases are influenced by factors that control the stability of neural function. Yet the mechanisms that dictate neural excitation and inhibition are poorly understood. Many studies indicate that homeostatic signaling mechanisms participate in the regulation of neural function, in particular by modulating the strength of synaptic connections. This project aims to clarify the mechanisms of synaptic homeostatic signaling. BACKGROUND/RATIONALE: We published a study demonstrating a role in synaptic homeostasis for an Ephexin signaling system. Ephexin is a Rho-type guanine exchange factor (GEF). Drosophila Ephexin is required presynaptically for synaptic homestasis and localizes in proximity of other components of the nerve terminal. Downstream of Ephexin GEF function, Rho-type GTPases are important for executing homeostatic compensation, in particular Cdc42. Upstream of Ephexin, the Drosophila Eph receptor (Eph) binds Ephexin and Eph mutants have impaired synaptic homeostasis. Components of this signaling system show strong genetic interactions with each other and with CaV2.1 calcium channel mutants. We postulate that this presynaptic signaling system couples homeostatic retrograde signaling at the synaptic plasma membrane to the modulation of presynaptic CaV2.1 function and neurotransmitter release. R00 PHASE DESIGN: Candidate molecules already known in other systems to regulate calcium channel function and Eph/Ephexin/GTP signaling will be tested for roles in synaptic homeostasis. Molecules that do show a role in homeostasis will be placed into the context of our presynaptic signaling system. This work will utilize a combination of approaches for the three-year R00 phase: electrophysiological analysis of synaptic function, genetic mutant analyses, pharmacological inhibition of target molecules, analyses of gene expression and protein localization, transgenic rescue, and genetic epistasis and pathway analyses. TRAINEES: New recruited members of my laboratory will be trained in all aspects of this project. Over the course of three years, this may include a technician, two graduate students, and a postdoctoral fellow.

Public Health Relevance

Many neurological diseases result from nervous system instability, but it is not understood how neural stability is normally maintained. Data show that a molecule called Ephexin associates with other molecules to help direct neural stability. We aim to clarify exactly how Ephexin performs this function;the results may ultimately lead to a better understanding of the cause, progression, and treatment of neural diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS062738-05
Application #
8231539
Study Section
Special Emphasis Panel (NSS)
Program Officer
Talley, Edmund M
Project Start
2008-07-15
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$234,375
Indirect Cost
$78,125
Name
University of Iowa
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Brusich, Douglas J; Spring, Ashlyn M; James, Thomas D et al. (2018) Drosophila CaV2 channels harboring human migraine mutations cause synapse hyperexcitability that can be suppressed by inhibition of a Ca2+ store release pathway. PLoS Genet 14:e1007577
Spring, Ashlyn M; Brusich, Douglas J; Frank, C Andrew (2016) C-terminal Src Kinase Gates Homeostatic Synaptic Plasticity and Regulates Fasciclin II Expression at the Drosophila Neuromuscular Junction. PLoS Genet 12:e1005886
Koles, Kate; Messelaar, Emily M; Feiger, Zachary et al. (2015) The EHD protein Past1 controls postsynaptic membrane elaboration and synaptic function. Mol Biol Cell 26:3275-88
Stephan, Raiko; Goellner, Bernd; Moreno, Eliza et al. (2015) Hierarchical microtubule organization controls axon caliber and transport and determines synaptic structure and stability. Dev Cell 33:5-21
Inagaki, Akira; Frank, C Andrew; Usachev, Yuriy M et al. (2014) Pharmacological correction of gating defects in the voltage-gated Ca(v)2.1 Ca²? channel due to a familial hemiplegic migraine mutation. Neuron 81:91-102
Frank, C Andrew (2014) Homeostatic plasticity at the Drosophila neuromuscular junction. Neuropharmacology 78:63-74
Frank, C Andrew; Wang, Xinnan; Collins, Catherine A et al. (2013) New approaches for studying synaptic development, function, and plasticity using Drosophila as a model system. J Neurosci 33:17560-8
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