Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices of GABABI receptor subunit knockout mice

The recently developed GABA(B1) receptor subunit knockout (GABA(B1)-/-) mouse displays complete loss of GABA(B) receptor function and develops complex generalized epilepsies including absence type, audiogenic as well as spontaneous generalized seizures with electrographic spike-wave discharge signatures. To gain insight into the cellular mechanisms contributing to the generation and maintenance of this epileptic phenotype we have compared epileptiform activity induced in hippocampal slices obtained from GABA(B1)-/- and wild type (GABA(B1)+/+) littermates. Deletion of the GABA(B1) receptor subunit had no effect on a ran-e of passive membrane properties of CA3 pyramidale neurones, non-synaptic epileptiform field bursting and spreading depression recorded in 6 mM (K)+/Ca2+-free medium, and inter-ictal synaptically-induced epileptiform activity induced by 100 muM 4-aminopytridine (4-AP). In contrast, synaptic epileptiform, activity induced by 10 muM bicuculline, removal of extracellular MG(2+) or addition of 10 muM oxotremorine was enhanced in GABA(B1)-/- slices. Acute blockade of GABA(B) receptors using a selective antagonist only partly mimicked these effects. It is suggested that the exaggerated in vitro epileptiform activity is caused by both acute and chronic consequences of the loss of GABA(B) receptor function in vivo. Specifically, enhancement of N-methyl-D-aspartate (NMDA) receptor triggered synaptic processes, arising from the loss of the GABA(B) receptor-mediated inhibitory postsynaptic potential (IPSP, together with a possible promotion of depolarising IPSPs due to the removal of GABA(B) autoreceptor function) is likely to underlie these effects. (C) 2003 Elsevier B.V. All rights reserved.