Axon‐to‐glia signalling is mediated by n‐acetylaspartylglutamate (NAAG) in crayfish

Abstract

Action potential generation in the medial giant axon of the crayfish causes the associated periaxonal glia to hyperpolarize by mechanisms sensitive to metabotropic glutamate receptor (mGLUR) and cholinergic receptor blockade. This response can be mimicked by the application of nanomolar NAAG or glutamate (GLU). Axons and glia synthesize NAAG from GLU or glutamine (GLN) and release it during electrical stimulation of the axon. NAAG is hydrolyzed to N‐acetylaspartate and GLU by glutamate carboxypeptidase II (GCPII), whose activity is increased by nerve fiber stimulation. When GCPII activity is blocked pharmacologically, NAAG's electrophysiological action on the glia is mediated solely by Group II mGLURs. When the enzyme is activated, GLU, the hydrolysis product of NAAG, contributes to glial hyperpolarization through a mechanism sensitive to NMDA receptor blockade. Both NAAG and GLU cause an increase in glial Ca2+ that may be a common link to a transduction cascade that hyperpolarizes glia by reducing Cl– permeability. A consequence of these changes is the modulation of K+ homeostasis of the neuronal microenvironment, preserving the ability of the axon to generate impulses at high frequency. GLU formed by NAAG hydrolysis is avidly accumulated by periaxonal glia, where it is converted to GLN and NAAG. The uptake of GLN and conversion to GLU and NAAG by axons provides a possible mechanism for recycling of the axon‐to‐glia signalling agent(s) in crayfish nerve fibers. Together, these results suggest that NAAG is the primary axon‐to‐glia signalling agent and source of signalling GLU at nonsynaptic regions of crayfish nerve fibers.Acknowledgements: Supported by NIH grant NS34799 and Guilford Pharmaceuticals (Baltimore, MD).