Vol. 303, Issue 3, 1102-1113, December 2002

Epileptiform Synchronization and GABA_B Receptor Antagonism in the Juvenile Rat Hippocampus

Rita Motalli, Margherita D'Antuono, Jacques Louvel, Irene Kurcewicz, Giovanna D'Arcangelo, Virginia Tancredi, Mario Manfredi, René Pumain and Massimo Avoli

Montreal Neurological Institute and Departments of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (R.M., M.A.); Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli (Isernia), Italy (M.D., M.M., M.A.); Centre Paul Broca and Institut National de la Santé et de la Recherche Médicale U109, Paris, France (J.L., I.K., R.P.); and Dipartimento di Neuroscienze, Università degli Studi di Roma "Tor Vergata", Roma, Italy (G.D., V.T.)

The GABA_B receptor agonist baclofen enhances the epileptiform activity induced by 4-aminopyridine (4AP) in juvenile rat hippocampal slices. In this study, we used a similar experimental approach (i.e., field potential, intracellular, and [K⁺]_o recordings in the CA3 area of slices obtained from 15-23-day-old rats) to establish whether antagonizing GABA_B receptors could exert opposite (presumably anticonvulsant) effects. Bath application of 4AP (50 µM) induced spontaneous interictal and ictal discharges along with synchronous GABA receptor-mediated potentials. All types of 4AP-induced synchronous activity occurred more frequently during application of the GABA_B receptor antagonist p3-amino-propyl,p-diethoxymethylphosphonic acid (CGP 35348) (0.1-1 mM; EC₅₀ = 0.25 mM). Moreover, CGP 35348 augmented the frequency and, to a lesser extent, the duration of the asynchronous synaptic activity recorded intracellularly from CA3 pyramids (n = 19). In medium containing 4AP + ionotropic glutamatergic antagonists (which abolished interictal and ictal activity), CGP 35348 prolonged both GABA-receptor-mediated field potentials and the accompanying intracellular long-lasting depolarizations without modifying their rate (n = 12). The transient elevations in [K⁺]_o associated with GABA receptor-mediated potentials in 4AP-containing medium (n = 7 slices) became larger during CGP 35348 application. Similar findings were obtained when CGP 35348 was applied to medium containing 4AP + ionotropic glutamatergic antagonists (n = 6). Thus, the effect of CGP 35348 on 4AP-induced epileptiform activity is not anticonvulsant and to some extent similar to what was reported in this model during GABA_B receptor activation. We propose that the facilitation of ictal activity by CGP 35348 is mainly caused by the blockade of presynaptic GABA_B receptor, leading to an increase in GABA release and subsequent larger [K⁺]_o elevations.