Modulation of Glutamate AMPA Receptor by Polysialic Acid

Tuskegee University, Tuskegee Institute AL

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Abstract

DESCRIPTION (provided by applicant): Alpha-amino-3-hydroxy-5-methlisoxazole-4-propionic acid (AMPA) sub-type of glutamate receptors play a major role in synaptogenesis and synaptic plasticity in mammalian central nervous system. Thus the mechanism and factors that modulate the functionality of these receptors are of considerable interest. Numerous reports demonstrate that the neural cell adhesion molecule (NCAM) carrying polysialic acid (PSA) and heparin sulfate proteoglycans (HSPG) bearing heparin sulfate (HS) play crucial roles in synaptogenesis and synaptic plasticity. The focus of this project is to determine the modulatory affects PSA on AMPA receptor functionality. The long-term objective is to elucidate the role of PSA interaction with AMPA receptors during synaptogenesis and synaptic plasticity. Specifically we aim to define the interaction between AMPA receptors and PSA in hippocampus and cortical regions of the brain utilizing electrophysiological and biochemical techniques. Electrophysiological analysis of purified AMPA receptors and isolated synaptosomes from postnatal and adult animals incorporated into lipid bilayers will also be performed. Identification of subunit composition and splicing isoforms required for PSA interaction with AMPA receptors will be carried out by expressing GluR 1-4 (homomeric and heteromeric) channels and flip flop isoforms in HEK 293 cells. Single channel analysis will be performed on expressed receptor combinations in the presence of FSA. Investigation into induction of AMPAR clustering and cooperative channel gating by PSA during synaptogenesis will be carried out. This project will exceed the basic understanding of PSA-AMPA receptor interaction and shed light into unique regulation(s) by which synaptic strengthening could occur.