Abstract
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 μ-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.
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