GABA(B) receptor activation and limbic network ictogenesis.
Rat brain slices containing interconnected hippocampus and entorhinal cortex (EC) responded to 4-aminopyridine (50 microM) application by generating: (i) CA3-driven interictal discharges that propagated to the EC; and (ii) N-methyl-D-aspartic (NMDA) acid receptor-dependent ictal events originating in EC (cf. J. Neurosci. 17 (1997) 9308 for experiments made in brain slices). Ictal discharges disappeared within 1-2 h, but were re-established by cutting the Schaffer collaterals, which abolished CA3-driven interictal discharge propagation to EC. In intact slices, GABA(B) receptor activation by baclofen (5-40 microM): (i) depressed CA3-driven interictal activity; and (ii) disclosed non-NMDA glutamatergic receptor-dependent ictal discharges originating in CA3 and propagating to EC. These effects were reversed by the GABA(B) receptor antagonist CGP 35348 (0.5 mM). Application of increasing baclofen doses to slices in which hippocampus and EC networks were surgically isolated decreased epileptiform events with an IC50 that was lower in EC (0.6 microM; n = 12) than in CA3 (2.5 microM; n = 12). Hence, under control conditions, EC ictogenesis depends on NMDA receptor function and is controlled by CA3-driven output activity; in contrast, following GABA(B) receptor activation EC excitability is depressed to a greater extent than CA3, which leads to non-NMDA glutamatergic receptor-mediated ictogenesis in CA3. We propose that GABA(B) receptor modulation may represent an important mechanism for setting the site of initiation, the modalities of propagation and the glutamatergic receptor properties of ictogenesis in the limbic system and, perhaps, in mesial temporal lobe epilepsy patients.
Avoli
Massimo
M
Departments of Neurology and Neurosurgery, and of Physiology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4. toula.papadopoulos@mcgill.ca
Benini
Ruba
R
de Guzman
Philip
P
Omar
Amer
A
D015761:4-Aminopyridine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D003714:Denervation / Q000379:methods; D004305:Dose-Response Relationship, Drug; D018728:Entorhinal Cortex / Q000187:drug effects / Q000502:physiology*; D005071:Evoked Potentials / Q000187:drug effects / Q000528:radiation effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology; D019580:Perforant Pathway / Q000293:injuries; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology*; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D026902:Potassium Channel Blockers; D018080:Receptors, GABA-B; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C066430:CGP 35348; D015761:4-Aminopyridine; D001418:Baclofen