Group I metabotropic glutamate receptors reduce excitotoxic injury and may facilitate neurogenesis

Neuropharmacology. 2005;49 Suppl 1:146-56. doi: 10.1016/j.neuropharm.2005.04.029.

Abstract

Group I metabotropic glutamate receptor (mGluR) agonist DHPG reduced nerve cell death caused by their exposure to NMDA ("neuroprotective effect") and attenuated NMDA receptor-mediated currents [Blaabjerg, M., Baskys, A., Zimmer, J., Vawter, M. P., 2003b. Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors. Brain Research, Molecular Brain Research 117, 196-205.]. In the present study, we used organotypic hippocampal culture preparation to examine specific phospholipase C (PLC) inhibitor U73122 effects on DHPG-induced neuroprotection, changes in excitatory synaptic transmission associated with the neuroprotective DHPG treatment and a role of group I mGluR ligands in neurogenesis. Results show that short (10 min) DHPG treatment did not result in neuroprotection but significantly depressed field synaptic potentials (fEPSP) in the Schaffer collateral-CA1 pathway. The fEPSP depression was not affected by the PLC inhibitor U73122. In contrast, prolonged (2-h) treatment of cultures with DHPG induced a significant protective effect that was blocked by a PLC inhibitor U73122 but not by its inactive analog U73343. Voltage-clamp measurements of spontaneous miniature excitatory post-synaptic currents (EPSCs) recorded in CA1 neurons from cultures treated with DHPG (10 microM, 2 h) showed a significant reduction of the EPSC amplitude in DHPG-treated but not control (untreated) cultures. This reduction was completely abolished by U73122, suggesting a PLC involvement. Since activation of PLC is thought to be associated with cell proliferation, we investigated whether group I mGluR agonist DHPG or subtype antagonists LY367385 and MPEP have an effect on dentate granule cells expressing immature neuronal marker TOAD-64. DHPG (100 microM, 72 h) slightly but not significantly increased the number of TOAD-64 positive cells. The mGluR1 antagonists LY367385 (10 microM, 72 h) markedly decreased the number of TOAD-64 positive cells and mGluR5 antagonist MPEP (1 microM, 72 h) had no effect. These data suggest that (1) prolonged activation of group I mGluRs reduces nerve cell susceptibility to excitotoxic injury in a PLC-dependent manner; (2) this reduction is associated with a PLC-dependent depression of excitatory synaptic transmission; and (3) mGluR1 activation may facilitate neurogenesis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Benzoates / pharmacology
  • Cell Count / methods
  • Cell Death / drug effects
  • Dose-Response Relationship, Radiation
  • Drug Interactions
  • Electric Stimulation / methods
  • Estrenes / pharmacology
  • Excitatory Amino Acid Agonists / toxicity*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Gene Expression Regulation / drug effects
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / injuries
  • Hippocampus / physiology*
  • Immunohistochemistry / methods
  • In Vitro Techniques
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Models, Biological
  • N-Methylaspartate / toxicity*
  • Nerve Tissue Proteins / metabolism
  • Patch-Clamp Techniques / methods
  • Phosphodiesterase Inhibitors / pharmacology
  • Propidium
  • Pyrrolidinones / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / physiology*

Substances

  • Benzoates
  • Dpysl3 protein, rat
  • Estrenes
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Nerve Tissue Proteins
  • Phosphodiesterase Inhibitors
  • Pyrrolidinones
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • U 73343
  • alpha-methyl-4-carboxyphenylglycine
  • Propidium
  • Methoxyhydroxyphenylglycol
  • N-Methylaspartate
  • Glycine
  • 3,4-dihydroxyphenylglycol