Abstracts

RATIONALE: Seizures occur more frequently in infancy than at any other time in life. Prolonged seizures in early development result in significantly less structural damage than seizures in adult animals. Potential long-term subcellular and molecular effects of early life seizures, however, are not well elucidated. We examined the effects of status epilepticus (SE) at postnatal day 10 (P10) in rats on later seizure threshold and expression of excitatory and inhibitory neurotransmitter receptors and transporters in hippocampal neurons to better understand potential long-term consequences of early-life status epilepticus.
METHODS: On P10 rat pups were subjected to lithium-pilocarpine induced SE. Occurrence of SE was confirmed by EEG and behavioural monitoring. At P90, antisense RNA amplification (aRNA) techniques were used to examine the expression of different GABA(A) receptor (GABAR), NMDA receptor, AMPA receptor (GluR), Glutamate (GluT) and GABA (GAT) transporter mRNAs in single hippocampal dentate granule cells (DGC) from pilocarpine-treated and lithium-injected, identically handled littermate controls. Brains were subsequently examined for cell loss and synaptic reorganization using cresyl violet and Timm staining. Threshold for seizure induction by kainic acid (KA) tail-vein infusion at P90 was determined in a separate set of P10 pilocarpine-treated and lithium control animals.
RESULTS: Relative mRNA expression (compared to [beta]-actin) of GABAR [alpha]1 subunit was increased 3-fold (p[lt]0.001), GABAR [beta] 1 subunit was increased 1.5-fold (p[lt]0.01), the neuronal GluT EAAC1 was increased 6-fold (p[lt]0.001), and GAD67 was increased 3-fold (p[lt]0.001) in DGCs from adult rats subjected to pilocarpine-induced SE at P10 compared to DGCs from age-matched, sham treated littermate control rats. Combined expression of all GluR subunit mRNAs was also increased 1.5-fold (p[lt]0.05), while total GAT mRNA expression (compared to [beta]-actin) was decreased 2-fold (p[lt]0.05) in DGCs from pilocarpine treated rats compared to controls. P10 pilocarpine-treated rats had a lower seizure threshold, requiring 50% less KA to induce first electrographic seizure (15.67 [plusminus] 1.6 mg/Kg ) compared to controls (7.96 [plusminus] 0.95 mg/Kg, p[lt]0.05). Timm and cresyl violet staining did not show any evidence of synaptic reorganization or hippocampal cell loss in pilocarpine-treated rats.
CONCLUSIONS: The data from this study demonstrate long-term molecular alterations in hippocampal neurons following early-life status epilepticus which may contribute to a chronically lowered seizure threshold.
[Supported by: NIH NS38595 and Epilepsy Foundation of America to ABK]