Group I mGluR-mediated silent induction of long-lasting epileptiform discharges.
Picrotoxin, an antagonist of GABA(A) receptor-mediated activity, elicited 320- to 475-ms synchronized bursts from the CA3 region of the guinea pig hippocampal slice. The addition of the selective group I metabotropic glutamate receptor (mGluR) agonist (S)-3, 5-dihydroxyphenylglycine (DHPG, 50 microM; 20- to 45-min application) gradually increased the burst duration to 1-4 s; this effect persisted 2-3 h after agonist removal. To determine whether the induction of this long-lasting effect required ongoing synchronized activity during mGluR activation, DHPG application in a second set of experiments took place in the presence of CNQX and (R, S)-CPP, antagonists of AMPA/kainate and NMDA receptors, respectively. In these experiments, synchronized bursting was silenced during the mGluR agonist application, yet after wash out of the DHPG and the ionotropic glutamate receptor (iGluR) blockers, epileptiform discharges 1-10 s in duration appeared and persisted at least 2 h after wash out of the mGluR agonist. The potentiated bursts were reversibly shortened by application of 500-1,000 microM (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) or (S)-4-carboxyphenylglycine (4CPG), agents with group I mGluR antagonist activity. These data suggest that transient activation of group I mGluRs, even during silencing of synchronized epileptiform activity, may have an epileptogenic effect, converting brief interictal-length discharges into persistent seizure-length events. The induction process is iGluR independent, and the maintenance is largely mediated by the action of endogenous glutamate on group I mGluRs, suggesting that autopotentiation of the group I mGluR-mediated response may underlie the epileptogenesis seen here.
Merlin
L R
LR
Department of Neurology and Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York 11203, USA.
D000818:Animals; D004827:Epilepsy / Q000139:chemically induced*; D005071:Evoked Potentials / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008734:Methoxyhydroxyphenylglycol; D010852:Picrotoxin; D018094:Receptors, Metabotropic Glutamate; C010117:3,4-dihydroxyphenylglycol