title: An activity-dependent switch from facilitation to inhibition in the control of excitotoxicity by group I metabotropic glutamate receptors.
abstract: Activation of group I metabotropic glutamate receptors (mGlu1 or -5 receptors) is known to either enhance or attenuate excitotoxic neuronal death depending on the experimental conditions. We have examined the possibility that these receptors may switch between two different functional modes in regulating excitotoxicity. In mixed cultures of cortical cells, the selective mGlu1/5 agonist, 3,5-dihydroxyphenylglycine (DHPG), amplified neurodegeneration induced by a toxic pulse of NMDA. This effect was observed when DHPG was either combined with NMDA or transiently applied to the cultures prior to the NMDA pulse. However, two consecutive applications of DHPG consistently produced neuroprotection. Similar effects were observed with DHPG or quisqualate (a potent agonist of mGlu1/5 receptors) in pure cultures of cortical neurons virtually devoid of astrocytes. In cultures of hippocampal pyramidal neurons, however, only protective effects of DHPG were seen suggesting that, in these particular cultures, group I mGlu receptors were endogenously switched into a "neuroprotective mode". The characteristics of the activity-dependent switch from facilitation to inhibition were examined in mixed cultures of cortical cells. The switch in the response to DHPG was observed when the two applications of the drug were separated by an interval ranging from 1-45 min, but was lost when the interval was extended to 90 min. In addition, this phenomenon required the initial activation of mGlu5 receptors (as indicated by the use of subtype-selective antagonists) and was mediated by the activation of protein kinase C. We conclude that group I mGlu receptors are subjected to an activity-dependent switch in regulating excitotoxic neuronal death and, therefore, the recent "history" of these receptors is critical for the response to agonists or antagonists.
authors.affiliation: I.N.M. Neuromed, Località Camerelle, 86077 Pozzilli, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Bruno
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: A
authors.initials: A
authors.lastname: Copani
authors.forename: V M
authors.initials: VM
authors.lastname: Cespédes
authors.forename: M F
authors.initials: MF
authors.lastname: Galindo
authors.forename: V
authors.initials: V
authors.lastname: Ceña
authors.forename: J
authors.initials: J
authors.lastname: Sánchez-Prieto
authors.forename: F
authors.initials: F
authors.lastname: Gasparini
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
authors.forename: P J
authors.initials: PJ
authors.lastname: Flor
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000506:poisoning; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000506:poisoning; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009433:Neural Inhibition / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D016318:Quisqualic Acid / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C104077:metabotropic glutamate receptor type 1; C079215:3,5-dihydroxyphenylglycine; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D011493:Protein Kinase C; D005998:Glycine