Abstracts

Rationale: Temporal lobe epilepsy (TLE) is the most common type of partial complex epilepsy, and involves the hippocampus, parahippocampal regions and the temporal neocortex. Among these, the subiculum is of particular interest for TLE pathogenesis due to its powerful GABAergic inhibition, which endows this region with a gating role of hippocampal outputs (Benini and Avoli. J Physiol 566:885-900, 2005). Notably, in epileptic tissue, the subiculum appears to reinforce ictal-like synchronization (Panuccio et al. Neurobiol Dis, 2010. doi:10.1016/j.nbd.2010.05.003). Although the implication of GABAergic inhibition in TLE pathogenesis has been evidenced by several studies, none of these has focused on the changes occurring in the subiculum following an epileptogenic insult before the establishment of TLE (latent period). Here, we analyzed spontaneous GABA_A-mediated inhibitory post-synaptic currents (GABA_A-sIPSCs) generated by subicular neurons in pilocarpine-treated and non-epileptic control (NEC) tissue. Methods: Horizontal brain slices 300 ?m thick were obtained from male, adult Sprague-Dawley rats, 3-6 days after either pilocarpine-induced status epilepticus (SE) lasting 2 hours or after sham injection. Whole-cell patch-clamp recordings of pharmacologically isolated GABA_A-sIPSCs were performed from visually identified subicular principal neurons in symmetric chloride condition at a holding potential of -70 mV. Data were compared with the unpaired t-test and considered significantly different if p<0.05. Values are expressed as mean SEM. Results: Subicular neurons of pilocarpine-treated animals generated GABA_A-sIPSCs which occurred at rates similar to those in NEC tissue (mean interval - NEC: 0.84 0.35 s, n= 18; pilocarpine: 0.73 0.22 s, n= 12). Moreover, current density was similar in NEC (4.34 0.66 pA/pF, n= 18) and pilocarpine-treated subicular neurons (4.96 0.59 pA/pF, n= 12). However, GABA_A-sIPSCs generated by the latter cells were characterized by a significantly slower decay time constant (NEC: 6.87 0.57 ms, n= 18; pilocarpine: 10.86 1.51 ms, n= 12; p= 0.006), a larger charge transfer, Q/Cm (NEC: 26.32 3.76 pA*ms/pF, n= 18; pilocarpine: 56.11 13.21 pA*ms/pF, n= 12; p= 0.012), and a prolonged half-width (NEC: 4.24 0.44 ms, n= 18; pilocarpine: 7.27 1.34 ms, n= 12; p= 0.015). Overall, these changes in current kinetics resulted in a significant increase of the average total current, calculated as Q/Cm*IPSCs frequency (NEC: 0.11 0.03 pA, n= 18; pilocarpine: 0.23 0.09 pA, n= 12; p<0.001). Conclusions: Generation of GABA_A-sIPSCs is not impaired in subicular principal neurons following pilocarpine-induced SE. However, in spite of no apparent change in current density and sIPSCs frequency, a paradoxical enhancement of the average total current is brought about by the slower current kinetics. We propose that this phenomenon represents an early compensatory mechanism to counteract the documented interneuron loss, which would otherwise allow the spread of excitation from the hippocampus proper to parahippocampal areas.