Group I metabotropic glutamate receptors reduce excitotoxic injury and may facilitate neurogenesis.
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.
Baskys
Andrius
A
Department of Mental Health, VA Health Care System, Mental Illness Research and Education Clinical Center, Long Beach, University of California at Irvine, 06/116A, 5901 East Seventh Street Long Beach, CA, 90822 Irvine, CA, USA. andrius.baskys@med.va.gov
Bayazitov
Ildar
I
Fang
Liwei
L
Blaabjerg
Morten
M
Poulsen
Frantz Rom
FR
Zimmer
Jens
J
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001565:Benzoates / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004963:Estrenes / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000293:injuries / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D008954:Models, Biological; D016202:N-Methylaspartate / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011419:Propidium; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*
D001565:Benzoates; C449760:Dpysl3 protein, rat; D004963:Estrenes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C074854:U 73343; C079694:alpha-methyl-4-carboxyphenylglycine; D011419:Propidium; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; D005998:Glycine; C010117:3,4-dihydroxyphenylglycol