NAAG and NAALADase influence NMDA receptor activation and axon‐to‐glia signalling in crayfish medial giant nerve fibers

Abstract

Action potential generation in crayfish giant nerve fibers causes a transient depolarization followed by a prolonged hyperpolarization in their associated glial cells. The glial potential changes, involving a nicotinic acetylcholine receptor (nAChR)‐induced decrease in Cl– permeability, are caused by axonal release of N‐acetylaspartylglutamate (NAAG) acting specifically on glial group II metabotropic glutamate (mGLURII). In addition, GLU formed by NAAG hydrolysis by NAALADase acts on NMDARs as well as mGLURs. Application of NMDA or l‐aspartate also produces glial cell hyperpolarization that can be inhibited by antagonists of NMDA receptors (MK801) but not by antagonists of AMPA/kainate (AP4) or mGLURs (EGLU). Reducing extracellular Ca2+ depresses the NMDA effect while Na+ depletion, block of voltage‐dependent Ca2+ channels (verapamil) or the nAChR (d‐tubocurarin) completely prevent the response to NMDA. The hyperpolarization caused by high frequency stimulation of the nerve fiber is only partially reduced by NMDAR blockade suggesting these receptors are not solely responsible for initiating the glial hyperpolarization under physiological conditions. These results also indicate that the transient depolarization, induced by physiological activation of glial NMDARs, opens voltage‐sensitive Ca2+ channels leading to Ca2+ influx. An increase in [Ca2+]i by this mechanism potentiates the ACh release due to mGLURII activation and the subsequent hyperpolarization mediated by the nAChR.Acknowledgements: Supported by NIH grant NS34799 and Guilford Pharmaceuticals, Baltimore, MD, USA.