Spontaneous epileptiform activity mediated by GABA(A) receptors and gap junctions in the rat hippocampal slice following long-term exposure to GABA(B) antagonists.

Recent evidence suggests that excessive GABA(A) receptor-mediated transmission can lead to neuronal hyperexcitability and hypersynchrony. We show now that exposure of a rat hippocampal slice to GABA(B) receptor antagonists (CGP 55845A and CGP 35348) in the absence of ionotropic glutamatergic transmission leads to a progressive synchronization of spontaneous interneuronal activity. In about 30% of over 200 slices examined, the GABA(A)-mediated spontaneous activity produced field responses in the CA1 soma region with a positive-going phase of up to 5 mV, followed by a long-lasting negative deflection with a simultaneous extracellular K(+) transient. These bicarbonate-dependent GABAergic ictal-like events (GIEs) were associated with biphasic (hyperpolarizing/depolarizing) intracellular responses and with synchronous bursting of the pyramidal neurons. The GIEs could not be reversed by wash-out of the GABA(B) receptor antagonists or by baclofen, but they were inhibited by agonists acting on presynaptic mu-opioid and cannabinoid (CB1) receptors pointing to a down-regulation of presynaptic GABA(B) receptors. GIEs were dependent on intracellular carbonic anhydrase, and potentiated by maneuvers that increase intracellular pH. They were blocked by the Cx36-specific gap-junction (gj) blocker, quinine/quinidine, as well as by the broad-spectrum gj blocker, octanol. These data suggest that enhanced GABAergic activity with functional interneuronal connectivity via gjs is sufficient to trigger epileptiform activity in the absence of ionotropic glutamatergic transmission.