Since high concentrations of GABA are thought to exist in the synaptic cleft for only very brief periods of time (< 1 ms), effective synaptic GABAA receptors should activate very quickly and deactivate slowly. Within individual synapses, however, there is significant variability in the peak amplitude and duration of IPSCs that appears to be due to fluctuations in both peak GABA concentration and duration (Nusser et al. 2001; Mozrzymas, 2004). Similar to native receptors, the activation rates reported here were quite dependent on GABA concentrations (Maconochie et al. 1994) and were consistently slower for α4β3γ2L receptors during all but the highest GABA concentrations. Therefore, while the concentration time course of synaptic GABA may contribute to the shape of postsynaptic responses, our results suggest it may do so differently in α1β3γ2L and α4β3γ2L receptor-containing synapses. While multiple studies have found increased α4 subtype expression in epileptic animals (Schwarzer et al. 1997; Brooks-Kayal et al. 1998; Sperk et al. 1998), it is currently unclear whether this is associated with an increased number of α4 subtype-containing receptors that are actually within the synapses. One model of CNS hyperexcitability, chronic intermittent ethanol, produces animals with a lowered seizure threshold and an increased expression of α4 subunits in the hippocampus. In these animals, the subcellular localization of α4 subtype-containing receptors shifts from a primarily perisynaptic to a central synaptic location on dentate granule cells (Liang et al. 2006). If the same phenomenon proves true in epileptic animals, our results would predict that α4β3γ2L receptor-containing synapses would have attenuated peak currents during brief synaptic GABA. Our results also predict, however, that these responses would have prolonged decay times compared to α1β3γ2L currents, thus suggesting a possible compensatory role for up-regulation of α4 subtype-containing GABAA receptors. In the hippocampal dentate region of epileptic animals, there is a loss of interneurons and an associated reduction in IPSC frequency (Kobayashi & Buckmaster, 2003; Cohen et al. 2003; Naylor et al. 2005). The prolonged responses conveyed by α4 subtype-containing synapses may help to normalize the charge transfer over time. However, because of the observed coupling between desensitization and deactivation, α4βγ receptors are rendered relatively insensitive to prolonged repetitive stimulation, especially at frequencies above 2–5 Hz. Therefore, α4βγ receptors may serve as low pass frequency filters, which respond best to brief low frequency barrages of synaptic activity, but poorly to high frequency bursts of synaptic input. Similar to our findings, studies using brain slices have shown prolonged IPSCs in dentate granule cells during status epilepticus or chronic epilepsy (Cohen et al. 2003; Shao & Dudek, 2005; Naylor et al. 2005). However it is unknown what role, if any, enhanced α4 subtype expression plays in altered inhibitory neurotransmission in epileptic rats. One of the few reports describing the physiological significance of increased α4 subtype expression used recordings from CA1 pyramidal neurons following neurosteroid withdrawal. Pharmacological characterization of the IPSCs and comparison with recombinant GABAA receptors suggest that synaptic α1βγ GABAA receptors may be replaced by α4βγ and/or α4βδ receptors (Hsu et al. 2003; Smith & Gong, 2005). Interestingly, in contrast to our studies, the IPSCs in neurosteroid withdrawn neurons are significantly shortened. This discrepancy may be related to several technical differences, but one likely explanation is that the different findings are due to differences in the β subtype. Work in other models of epilepsy have also found accelerated IPSC decay in CA1 pyramidal neurons (Mangan & Bertram, 1997; Morin et al. 1998), where the predominant β subtype is β2. However, the enhanced α4 subtype expression in epileptic animals is found in the dentate gyrus where the β3 subtype is highly expressed. Consistent with this, preliminary work has found that the deactivation of α4β2γ2L currents is very brief compared to α4β3γ2L currents (Lagrange & Macdonald, 2005). Thus, the physiological consequences of α4 subtype expression may be very different from region to region, depending on the other GABAA receptor subtypes that are available for assembly.