GLYCINE CAUSES INCREASED EXCITABILITY AND NEUROTOXICITY BY ACTIVATIONOF NMDA RECEPTORS IN THE HIPPOCAMPUS

Glycine is an inhibitory neurotransmitter in the spinal cord and also acts as a permissive cofactor required for activation of the N-methyl- D-aspartate (NMDA) receptor. We have found that high concentrations of glycine (10 mM) cause marked hyperexcitability and neurotoxicity in o rganotypic hippocampal slice cultures. The hyperexcitability, measured using intracellular recording in CA1 pyramidal neurons was completely blocked by the NMDA receptor antagonist MK-801 (10 mu M), but not by the AMPA receptor antagonist DNQX (100 mu M) The neurotoxicity caused by glycine occurred in all regions of hippocampal cultures but was mos t marked in area CA1. There was significant CA1 neuronal damage in cul tures exposed to 10 mM glycine for 30 min or longer (P < 0.01) or thos e exposed to 4 mM glycine for 24 h compared to control cultures (P < 0 .01). The NMDA antagonists MK-801 (10 mu M) and APV (100 mu M) signifi cantly reduced glycine-induced neuronal damage in all hippocampal subf ields (P < 0.01). The AMPA antagonists CNQX, DNQX, and NBQX (100 mu M) had no effect on glycine-induced neuronal damage. High concentrations of glycine therefore appear to enhance the excitability of hippocampa l slices in an NMDA receptor-dependent manner. The neurotoxic actions of glycine are also blocked by NMDA receptor antagonists. (C) 1997 Aca demic Press.