Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices expressing a C-terminal truncated GABAB2 receptor subunit

GABAergic synaptic transmission plays an important role in the patterning of epileptiform activity. We have previously shown that global loss of GABAB receptor function due to transgenic deletion of the GABAB1 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 GABAB2 receptor subunit lacking its C terminal tail (the ΔGB2-Ct mouse); a molecular manipulation that also produces complete loss of GABAB receptor function. Thus, epileptiform bursts that are sensitive to NMDA receptor antagonists (induced by either the GABAA receptor antagonist bicuculline (10 μM) or removal of extracellular Mg2+) 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 GABAA 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 GABAB receptor function in ΔGB2-Ct hippocampal slices promotes depolarising GABAA receptor-mediated events, which in turn, leads to the generation of ictal-like events, which may contribute to the epilepsy phenotype observed in vivo.