Differential Modulation of Glutamatergic Synaptic Transmission by Polysialic Acid
Type of DegreeDissertation
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Controlled modulation and regulation of glutamate receptors are essential for synaptogenesis and synaptic plasticity. The two major types of excitatory glutamate receptors found at the synapse are AMPA and NMDA, which during over-activation leads to glutamate induced excitotoxicity. The functional properties of single synaptic receptors specifically NMDA receptors was characterized in detail in this study. The neural cell adhesion molecule (NCAM) is a glycoprotein that modulates synaptic plasticity. NCAM is covalently linked to polysialic acid (PSA), a negatively charged carbohydrate which is a polymer of sialic acid with an unusual a2, 8-linkage containing up to 200 residues. PSA-NCAM plays vital roles in the development of the nervous system and NMDA receptor-dependent synaptic plasticity in the adult. It is well known that carbohydrates play a vital role in cellular recognition and adhesive processes. There are several studies that established a link between PSA-NCAM and glutamate receptors. However, the mechanisms whereby PSA-NCAM modulates glutamate receptors have not been studied. Therefore, this study will investigate the effects of endogenous and soluble PSA-NCAM on synaptic glutamate receptors. Elucidating the functional properties of single synaptic glutamate receptors and the modulation of these receptors by PSA will be a step towards understanding many neurodegenerative disorders where PSA expression is altered. Synaptosomes and membrane fractions from rat hippocampi and recombinant receptors, respectively, were used in this study to evaluate the mechanistic effects of PSA on AMPA receptors and the NR2 subunit containing NMDA receptor subtypesNR2A, NR2B, and NR2A/NR2B, specifically. The hippocampi were isolated from 7-10 days old Sprague Dawley rats for synaptosomal preparation for synaptic AMPA receptor and NMDA receptor electrical recordings in the presence of specific receptor antagonist and agonists. Our results indicate that PSA potentiates synaptic AMPA receptor properties and that cyclothiazide, a known inhibitor of AMPA receptor desensitization does not occlude PSA effects on AMPA receptor activity. This indicates that PSA, in addition to decreasing the desensitization of AMPA receptors may also act through another mechanism. PSA also inhibited with the binding of glutamate to NR2B subunit-containing NMDA receptors. Furthermore, it is specific for the NR2B subunit and unlike other NR2B specific antagonists; PSA also inhibits NR2A/NR2B channels. PSA decreased the open probability and not the conductance of the NR2B subunit containing NMDA receptors. The results of our study reveal that 1) PSA potentiates AMPA receptor function and thereby possibly enhance synaptic plasticity, 2) inhibits NR2B containing NMDA receptors and thereby decreasing glutamate induced excitotoxicity.