Abstracts

Rationale: Status epilepticus (SE) is a neurological emergency characterized by a prolonged, self-sustained seizure. Previous studies have suggested a role for activity-dependent trafficking of GABA-A receptors as a possible mechanism that contributes to declining inhibition of principal neurons during SE. Studies investigating rapid presynaptic modifications at the interneuron-principal neuron synapse during SE have been limited. Methods: SE was induced in postnatal day 15 to 25 Sprague-Dawley male rats using lithium/pilocarpine (SE-treated). Acute hippocampal slices were prepared from SE-treated animals 1 hour after the first Racine stage 5 seizure. Whole cell ruptured membrane and loose patch clamp recordings were obtained from morphologically-identified dentate granule cells (DGC) as well as fast spiking basket cells (BC) located in close proximity to the dentate gyrus/hilus border. All recordings were completed within 2 hours of slice preparation. Results: The frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from DGCs in hippocampal slices obtained from SE-treated animals were reduced by 55% (SE-treated: 0.14 ± 0.03 Hz, n = 8 cells from 5 animals; control: 0.31 ± 0.04 Hz, n = 9 cells from 4 animals, p<0.05) and 31% (SE-treated: 35.55 ± 4.18 pA; control: 51.54 ± 6.50 pA, p<0.05), respectively. Since the decrease in sIPSC frequency could result, in part, from a reduced action potential (AP) firing frequency of interneurons, loose patch recordings of BCs were performed. The AP firing rate recorded from SE-treated BCs was reduced compared to controls by ~50% (SE-treated: 0.66 ± 0.12 Hz, n = 9 cells in 5 animals; control: 1.45 ± 0.19 Hz, n = 8 cells in 7 animals, p < 0.05). To investigate the mechanism of the reduction in firing rate, the tonic GABA current in SE-treated BCs was compared to controls. The tonic current, measured as the change in holding current after the application of SR95531 (50 μM), was increased in the SE-treated BCs (SE-treated: 17.01 ± 2.65 pA, n = 9 cells from 6 animals; control: 8.05 ± 1.95 pA, n = 9 cells from 8 animals, p < 0.05). Similar results were obtained following the application of picrotoxin (100 μM) (SE-treated: 31.21 ± 9.38 pA, n = 4 cells from 4 animals; control: 8.82 ± 3.92 pA; n = 5 cells from 4 animals, p < 0.05). Conclusions: SE is a dynamic process in which there is an associated decline in GABA-mediated inhibition. This study demonstrates an additional mechanism by which this decline may occurs; namely, a reduction in the AP firing frequency of BCs which synapse upon principal neurons of the dentate gyrus. The mechanism of this reduction was, in part, due to enhancement of the tonic GABA inhibition of BCs.