The Journal of Neurophysiology Vol. 82 No. 2 August 1999, pp. 638-647
Copyright ©1999 by the American Physiological Society

GABA_B Receptor Activation Promotes Seizure Activity in the Juvenile Rat Hippocampus

 ¹Montreal Neurological Institute, Department of Neurology and Neurosurgery, and Department of Physiology, McGill University, Montreal, Quebec H3A 2B4, Canada;  ²Centre Paul Broca, Institut National de la Santé et de la Recherche Médicale U109, 75014 Paris, France;  ³Dipartimento di Neuroscienze, Università degli Studi di Roma `Tor Vergata', 00173 Rome, Italy; and  ⁴Institut National de la Santé et de la Recherche Médicale U398, 67000 Strasbourg, France

Motalli, Rita, Jacques Louvel, Virginia Tancredi, Irène Kurcewicz, Doreen Wan-Chow-Wah, René Pumain, and Massimo Avoli. GABA_B Receptor Activation Promotes Seizure Activity in the Juvenile Rat Hippocampus. J. Neurophysiol. 82: 638-647, 1999. We analyzed how the GABA_B receptor agonist baclofen (10-50 µM) influences the activity induced by 4-aminopyridine (4-AP, 50 µM) in the CA3 area of hippocampal slices obtained from 12- to 25-day-old rats. Interictal and ictal discharges along with synchronous GABA-mediated potentials occurred spontaneously in the presence of 4-AP. Baclofen abolished interictal activity (n = 29 slices) and either disclosed (n = 21/29) or prolonged ictal discharges (n = 8/29), whereas GABA-mediated potentials occurred at a decreased rate. The N-methyl-D-aspartate (NMDA) receptor antagonist 3,3-(2-carboxypiperazine-4-yl)-propyl-1-phosphate (CPP, 10 µM, n = 8) did not modify the GABA-mediated potentials or the ictal events recorded in 4-AP + baclofen. In contrast ictal, activity, but not GABA-mediated potentials, was blocked by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 µM, n = 5). Most baclofen effects were reversed by the GABA_B receptor antagonist CGP 35348 (1 mM; n = 4). Baseline and transient increases in [K⁺]_o associated with the 4-AP-induced synchronous activity were unaffected by baclofen. Baclofen hyperpolarized CA3 pyramids (n = 8) recorded with K-acetate-filled electrodes by 4.8 ± 1.3 mV and made spontaneous, asynchronous hyperpolarizing and depolarizing potentials disappear along with interictal depolarizations. GABA-mediated synchronous long-lasting depolarizations (LLDs) and asynchronous depolarizations were also studied with KCl-filled electrodes in 4-AP + CPP + CNQX (n = 6); under these conditions baclofen did not reduce LLD amplitude but abolished the asynchronous events. Dentate hilus stimulation at 0.2-0.8 Hz suppressed the ictal activity recorded in 4-AP + baclofen (n = 8). Our data indicate that GABA_B receptor activation by baclofen decreases transmitter release leading to disappearance of interictal activity along with asynchronous excitatory and inhibitory potentials. By contrast, GABA-mediated LLDs and ictal events, which reflect intense action potential firing invading presynaptic inhibitory and excitatory terminals respectively, are not abolished. We propose that the proconvulsant action of baclofen results from 1) block of asynchronous GABA-mediated potentials causing disinhibition and 2) activity-dependent changes in hippocampal network excitability.