Mechanism of NMDA receptor contribution to axon-to-glia signaling in the crayfish medial giant nerve fiber.

Abstract

Electrical stimulation of crayfish giant axons at high frequency activates group II metabotropic and NMDA glutamate receptors on adjacent glial cells via release of N-acetylaspartylglutamate and glutamate formed upon its hydrolysis. This produces a transient depolarization followed by a prolonged hyperpolarization of glial cells that involves nicotinic acetylcholine receptor activation. The hyperpolarization is nearly completely blocked by antagonists of metabotropic glutamate receptors but only slightly reduced by inhibition of NMDA receptors. We report that the NMDA-induced hyperpolarization of glial cells is reduced by decreased calcium in the solution bathing the giant nerve fiber, while removal of sodium ions or block of voltage-dependent calcium channels completely prevents the glial response to NMDA. Inhibition of nicotinic acetylcholine receptors or removal of extracellular Cl(-) converts the glial response from a hyperpolarization to a depolarization that is sensitive to NMDA receptor antagonist. We propose that NMDA receptor activation by glutamate, formed from extracellular N-acetylaspartylglutamate during nerve stimulation, contributes to glial hyperpolarization by increasing intracellular Ca(2+) via opening of voltage-sensitive Ca(2+) channels. Based on our previous work, we propose further that the added Ca(2+) supplements that produced by N-acetylaspartylglutamate and glutamate acting on group II metabotropic glutamate receptors to cause an increased release of acetylcholine and a larger hyperpolarization.