Activation of group III metabotropic glutamate receptors by endogenous glutamate protects against glutamate-mediated excitotoxicity in the hippocampus in vivo

Perfusion of 4-aminopyridine (4-AP) by microdialysis in the hippocampus produces intense epileptiform behavioral and electrical activity and neurodegeneration, resulting from a stimulated release of glutamate from nerve endings. In contrast, accumulation of extracellular glutamate by blockade of its transport in vivo in anesthetized rats is innocuous, and studies in vitro in brain slices suggest that under these conditions glutamate may activate presynaptic group III metabotropic glutamate receptors (mGluRs) and inhibit its own release. Therefore, using microdialysis, EEG recording, and histological evaluation, we studied the effect of increased endogenous extracellular glutamate by blockade of its transport with pyrrolidine dicarboxylic acid (PDC) on the excitotoxic action of 4-AP in the hippocampus of awake rats. We found that up to a 20-fold increase in extracellular glutamate during >90 min with PDC does not induce any sign of excitotoxicity. On the contrary, this glutamate increase notably protected against the 4-AP-induced seizures and neurodegeneration, and, remarkably, this protection was dependent on the time of perfusion with PDC and thus on the duration of extracellular glutamate accumulation. To test whether this protective action was mediated by the activation of group III mGluRs, we used specific antagonists of these receptors and found that they clearly prevented the protective effect of PDC, without affecting the accumulation of extracellular glutamate. We conclude that the spillover of the excess extracellular glutamate activates presynaptic group III mGluRs and inhibits the stimulatory effect of 4-AP on its release, thus preventing the activation of postsynaptic N-methyl-D-aspartate receptors and its deleterious consequences.