Abstracts

RATIONALE: Seizures occur commonly in early childhood, and prolonged seizures have been associated with an increased incidence of temporal lobe epilepsy (TLE; Cendes et al. Ann. Neurol. 34: 795-801, 1993). However, potential mechanisms linking early life seizures to the subsequent development of epilepsy are not well understood. Previous studies from our laboratory suggest that 65% of rats will develop spontaneous seizures following lithium-pilocarpine induced status epilepticus (SE) at postnatal day 20 (P20), but only a small fraction of these epileptic animals show structural changes in the hippocampus such as cell loss and mossy fiber sprouting. Previous studies in animals with TLE following SE in adulthood support the importance of hippocampal GABA (A) receptor alterations. We therefore examined the functional properties of GABA (A) receptors in acutely isolated hippocampal dentate granule neurons (DGNs) of adult rats with spontaneous seizures following SE at P20. These studies should help elucidate potential mechanisms of epileptogenesis following early life seizures.
METHODS: Sprague-Dawley rat pups at P19 were injected with 3mEq/kg lithium chloride and on P20 with 60 mg/kg pilocarpine. Occurrence of SE in pilocarpine-treated pups was confirmed by EEG and behavioural monitoring. Rats were video-EEG monitored in adulthood ([gt] P90) to identify animals with spontaneous seizures. DGNs were acutely isolated from epileptic and age-matched, sham treated littermate control rats, and GABA(A) receptor currents were recorded at GABA concentrations of 3-1000 [mu]m using a whole cell patch clamp technique.
RESULTS: GABA efficacy was significantly lower at concentrations of 30 - 1000 [mu]m (p[lte]0.02). Maximal GABA evoked current (at 1000 [mu]m) in epileptic DGNs was 42% of that seen in DGNs from age-matched, sham treated littermate controls (382 [plusminus] 96 pA in epileptic DGN vs. 910 [plusminus] 155 pA in control DGN; p[lte]0.01).
CONCLUSIONS: Our earlier studies showed that morphological changes in the hippocampus were not a necessary prerequisite for occurrence of spontaneous seizures following pilocarpine-induced SE at P20. The present study suggests that long-term changes in GABA(A) receptor function in DGN occur following SE at P20 and could contribute to epilepsy development. Further, these data indicate that SE induced GABA(A) receptor changes are markedly age dependent. Previous studies of rats who develop TLE following SE in adulthood have demonstrated increased maximal GABA currents (Brooks-Kayal et al., Nature Med. 4: 1166-1172, 1998), incontrast to the decreased GABA maximal currents seen following early-life SE.
[Supported by: NIH NS38595 and Epilepsy Foundation of America to ABK]