THE NEUROPROTECTIVE ACTIVITY OF GROUP-II METABOTROPIC GLUTAMATE RECEPTORS REQUIRES NEW-PROTEIN SYNTHESIS AND INVOLVES A GLIAL-NEURONAL SIGNALING

The group-II metabotropic glutamate (mGlu) receptor agonists S,1'R,2'R ,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), S-4-carboxy-3-hydr oxyphenylglycine (4C3HPG), and (2S,1'S,2'S)-2-(carboxycyclopropyl)glyc ine (L-CCG-I) protected mouse cortical neurons grown in mixed cultures against excitotoxic degeneration induced by a 10 min pulse with NMDA. Protection was observed not only when agonists were added in combinat ion with NMDA but also when they were transiently applied to cultures 6-20 hr before the NMDA pulse. In both cases, neuroprotection was redu ced by the group-II mGlu receptor antagonist 'S,3'R)-2-(2'-carboxy-3'- phenylcyclopropyl)glycine (PCCG-IV), as well as by the protein synthes is inhibitor cycloheximide (CHX). Both neurons and astrocytes in mixed cultures were immunostained with an antibody that recognized mGlu2 an d mGlu3 receptors in recombinant cells. To determine whether astrocyte s played any role in the neuroprotection mediated by group-II mGlu rec eptors, we exposed pure cultures of cortical astrocytes to DCG-IV, 4C3 HPG, or L-CCG-I for 10 min. The astrocyte medium collected 2-20 hr aft er the exposure to any of these drugs was highly neuroprotective when transferred to mixed cultures treated with NMDA. This protective activ ity was reduced when CHX was applied to astrocyte cultures immediately after the transient exposure to group-II mGlu receptor agonists. We c onclude that neuroprotection mediated by group-II mGlu receptors in cu ltured cortical cells requires new protein synthesis and involves an i nteraction between neurons and astrocytes.