Abstracts

Rationale: The prolonged seizures of status epilepticus (SE) are self-sustaining and the probability of spontaneous termination in the absence of treatment is low. The pathogenesis of SE has not been completely elucidated. It is possible that multiple mechanisms may contribute to or result in these prolonged seizures. Recent studies have focused on the trafficking of GABAA receptors (GABARs) as one potential mechanism to explain the reduction in GABA-mediated inhibition that occurs during SE. These studies were performed predominantly following lithium-pilocarpine induction in adolescent and older animals. This study was undertaken to evaluate for age- and model-dependent differences in the pathogenesis of SE. Methods: SE was induced in postnatal (P) 15-17 and P23-25 SD rats induced by either lithium-pilocarpine (LiPilo-induction) or kainic acid (KA-induction). GABAR-mediated miniature synaptic currents (mIPSCs) were recorded using standard electrophysiological methods from dentate granule cells (DGCs) and CA1 pyramidal neurons (PN) in hippocampal slices acutely obtained from animals in SE (SE-treated) of 1 hour in duration and na ve controls. A biotinylation pull down assay was used to measure the surface expression of the ?2 subunit of the GABAR in whole hippocampal slices acutely obtained from SE-treated and control animals. Results: LiPilo-induction: The mean of the median mIPSC amplitude recorded from SE-treated DGCs following LiPilo-induction at P15-17 was smaller (34.7 3.1 pA, n =6 vs. 43.0 2.5 pA, n=8; p =0.055) and the surface expression of the ?2 subunit in the SE-treated slices was reduced (surface/total ratio = 0.4 0.1 vs. 0.7 0.2, n=5, p<0.05) compared to controls. A reduction in mIPSC amplitude (38.1 1.1 pA, n =3 vs. 47.5 3.1 pA, n=4, p <0.05) and ?2 subunit surface expression (0.3 0.1 vs. 0.7 0.1, n=5, p <0.05) was also observed following LiPilo-induction at P23-P25. KA-induction: The mIPSC amplitude recorded from SE-treated DGCs (53.8 5.5 pA, n = 9 vs. 47.5 3.1 pA, n= 8) and PNs (36.7 4.6 pA, n = 6 vs. 32.5 3.8 pA, n = 5) was similar to controls. The surface expression of the ?2 subunit in the SE-treated slices was also similar to controls (0.8 0.3 vs. 0.6 0.1, n =5). The mIPSC amplitude recorded form SE-treated DGCS following KA-induction at P23-25 were also similar to control (53.8 5.2 pA, n = 8 vs. 47.5 3.1 pA, n = 5) as was the surface expression of the ?2 subunit (0.4 0.1, n = 5 vs. 0.5 0.1, n = 5). Conclusions: These findings confirm and extend our previous findings of reduced GABA-mediated mIPSC amplitudes and surface expression of the benzodiazepine-sensitive ?2 subunit-containing GABARs following LiPilo-induced SE down to animals as young as P15. The unique finding is the absence of a similar reduction in mIPSC amplitude and ?2 subunit surface expression following KA-induced SE in animals as old as P25. Additional studies are required to evaluate GABA-mediated synaptic inhibition following KA-induced SE in older animals and to determine the treatment implications of this model-dependent difference.