mGluR7-like receptor and GABA(B) receptor activation enhance neurotoxic effects of N-methyl-D-aspartate in cultured mouse striatal GABAergic neurones.
Presynaptic metabotropic glutamate receptors (mGluRs) of group III constitute possible targets for putative neuroprotective drugs acting against glutamate excitotoxic insults. Indeed, in glutamatergic cerebellar granule neurones in culture, high concentrations of L-2-amino-4-phosphonobutyrate (L-AP4, above 0.3 mM, thus activating mGluR7) inhibit NMDA-induced cell death. In contrast, in striatal cultures which are enriched in GABAergic neurones, we show that high concentrations of L-AP4 increased neuronal death in control as well as in NMDA-stimulated cultures. Moreover, similar results were obtained with the GABA(B)R agonist. baclofen. Both the neuroprotective effects in cerebellar granule cells and the neurotoxic effects in striatal neurones were mediated via Gi-Go-coupled mGluRs, suggesting that these effects were probably mediated by mGluR7a or b and GABA(B)R expressed in these neurones. In striatal neurones, we found that L-AP4 and baclofen inhibited both basal and NMDA-stimulated GABA release. These inhibitions of GABA release may be responsible for the increase in basal and NMDA-stimulated neuronal death. Indeed, blockade of GABA(A) receptors with bicuculline increased neuronal death of control and NMDA-treated striatal cultures. Taken together, these results suggest that L-AP4 and baclofen, via mGluR7 and GABA(B)R, reduced the neuroprotective effect of GABA present in striatal cultures acting via GABA(A) receptors. Although caution must be taken when extrapolating from in vitro to in vivo situations, the present experiments and the recent observations that mGluR7 and GABA(B)R are expressed in heterologous synapses, should be taken into consideration when evaluating the neuroprotective action of future mGluR7 specific agonists or GABA(B)R specific antagonists.
Lafon-Cazal
M
M
CNRS-UPR 9023, CCIPE, Montpellier, France. lafon@ccipe.montp.inserm.fr
Viennois
G
G
Kuhn
R
R
Malitschek
B
B
Pin
J P
JP
Shigemoto
R
R
Bockaert
J
J
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D018698:Glutamic Acid / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity*; D011422:Propionates / Q000494:pharmacology*; D018080:Receptors, GABA-B / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C114785:2-amino-4-phosphono-propinate; D018690:Excitatory Amino Acid Agonists; D058786:GABA-B Receptor Agonists; D009498:Neurotoxins; D011422:Propionates; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D001418:Baclofen