Glycine Causes Increased Excitability and Neurotoxicity by Activation of NMDA Receptors in the Hippocampus

Abstract

Glycine is an inhibitory neurotransmitter in the spinal cord and also acts as a permissive cofactor required for activation of theN-methyl-d-aspartate (NMDA) receptor. We have found that high concentrations of glycine (10 mM) cause marked hyperexcitability and neurotoxicity in organotypic hippocampal slice cultures. The hyperexcitability, measured using intracellular recording in CA1 pyramidal neurons was completely blocked by the NMDA receptor antagonist MK-801 (10 μM), but not by the AMPA receptor antagonist DNQX (100 μM). The neurotoxicity caused by glycine occurred in all regions of hippocampal cultures but was most marked in area CA1. There was significant CA1 neuronal damage in cultures exposed to 10 mMglycine for 30 min or longer (P<0.01) or those exposed to 4 mMglycine for 24 h compared to control cultures (P<0.01). The NMDA antagonists MK-801 (10 μM) and APV (100 μM) significantly reduced glycine-induced neuronal damage in all hippocampal subfields (P<0.01). The AMPA antagonists CNQX, DNQX, and NBQX (100 μM) had no effect on glycine-induced neuronal damage. High concentrations of glycine therefore appear to enhance the excitability of hippocampal slices in an NMDA receptor-dependent manner. The neurotoxic actions of glycine are also blocked by NMDA receptor antagonists.