Synaptic regulation by EphA4 receptor signaling

Burnham Institute For Medical Research, La Jolla CA

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Abstract

DESCRIPTION (provided by candidate): The synapse is a specialized site of cell contact that regulates communication between neurons. Current belief is that information can be stored in the brain by creating, remodeling, and modifying the strength of synaptic contacts. Hence, elucidating the molecular mechanisms that partake in both normal and impaired synaptic physiology will significantly contribute to the understanding of many neural disorders. Recently, Eph receptor tyrosine kinases have been implicated in regulating the development and function of synapses in the vertebrate central nervous system. Interestingly, many of these receptors are enriched in regions of the adult brain that support synaptic plasticity changes, suggesting that they may function in synaptic signaling events. This proposal will focus on the role of the EphA4 receptor tyrosine kinase in synaptic function. Preliminary results have localized this receptor exclusively to postsynaptic regions on dendritic spines of hippocampal CAl pyramidal cells in vivo. This project will use a novel approach using 2-dimenisional gel electrophoresis combined with MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight) mass spectrometry to identify synapse specific proteins that interact with EphA4. Furthermore, mass spectrometry will be used to identify phosphorylated tyrosine residues of EphA4 in the adult hippocampus and determine if EphA4 phosphorylation is regulated by synaptic activity. Finally, I will investigate the physiological function of EphA4 in synapses by using a gene-trap mouse line with a defective EphA4 gene and by perturbing the function of the EphA4 PDZ-domain binding region and tyrosine phosphorylation sites.