Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices expressing a C-terminal truncated GABA B2 receptor subunit

Abstract

GABAergic synaptic transmission plays an important role in the patterning of epileptiform activity. We have previously shown that global loss of GABA B receptor function due to transgenic deletion of the GABA B1 receptor subunit exacerbates epileptiform activity induced by pharmacological manipulations in hippocampal slices. Here we show that a similar hyperexcitable phenotype is observed in hippocampal slices prepared from a transgenic mouse expressing a GABA B2 receptor subunit lacking its C terminal tail (the ΔGB2-Ct mouse); a molecular manipulation that also produces complete loss of GABA B receptor function. Thus, epileptiform bursts that are sensitive to NMDA receptor antagonists (induced by either the GABA A receptor antagonist bicuculline (10 μM) or removal of extracellular Mg 2+) were significantly longer in duration in ΔGB2-Ct slices relative to WT slices. We now extend these observations to demonstrate that a stimulus train induced bursting (STIB) protocol also evokes significantly longer bicuculline sensitive bursts of activity in ΔGB2-Ct slices compared to WT. Furthermore, synchronous GABA A receptor-mediated potentials recorded in the presence of the potassium channel blocker 4-aminopyridine (4-AP, 100 μM) and the ionotropic glutamate receptor antagonists NBQX (20 μM) and D-AP5 (50 μM) were significantly prolonged in duration in ΔGB2-Ct versus WT slices. These data suggest that the loss of GABA B receptor function in ΔGB2-Ct hippocampal slices promotes depolarising GABA A receptor-mediated events, which in turn, leads to the generation of ictal-like events, which may contribute to the epilepsy phenotype observed in vivo.