GABA(B) receptor activation promotes seizure activity in the juvenile rat hippocampus.
We analyzed how the GABA(B) receptor agonist baclofen (10-50 microM) influences the activity induced by 4-aminopyridine (4-AP, 50 microM) 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 microM, 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 microM, 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.
Motalli
R
R
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
Louvel
J
J
Tancredi
V
V
Kurcewicz
I
I
Wan-Chow-Wah
D
D
Pumain
R
R
Avoli
M
M
D015761:4-Aminopyridine / Q000494:pharmacology; D017668:Age of Onset; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology*; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D006624:Hippocampus / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced*
D003292:Convulsants; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D015761:4-Aminopyridine; D001418:Baclofen