Abstracts

Rationale: Febrile seizures (FSs) are the most common seizure in childhood and generally are of a benign nature. However, there is controversy about their association with later development of temporal lobe epilepsy. Many experimental studies rely on a hyperthermic model to mimic the human condition, which can lead to the development of spontaneous seizures in adulthood. However, as fever is a different physiologic process than hyperthermia, it is unclear whether similar consequences are seen after experimental FSs which rely on the host mounting a febrile response. Methods: Experimental FSs were induced in male Long-Evans rats on post-natal day 14 using the bacterial endotoxin lipopolysaccharide and what is normally a subconvulsant dose of kainic acid. Approximately 50% of rats receiving this treatment seized, providing a group of drug controls (DCs) for comparison. A separate group was also treated as saline controls (SCs). Rats were monitored behaviorally for manifestations of seizure, with a subset also undergoing EEG recordings. Seizure threshold testing took place eight weeks later with the chemical convulsant kainic acid. Another group of rats had electrodes implanted into the hippocampus or neocortex for continuous video-EEG monitoring to detect spontaneous seizures. Finally, a subset of rats had tissue dissected from the hippocampus for real-time reverse-transcription polymerase chain reaction (RT-PCR) with primers to detect GABA receptor subunits and the enzyme GAD67,glutamate receptor subunits, and cation chloride co-transporters. Results: Eight weeks after seizure induction adults who had a previous FS demonstrated a significantly decreased latency to seizure onset after injection of kainic acid compared with SCs. Continuous video-EEG recordings did not reveal the presence of spontaneous seizures or abnormal discharges in any group. Semi-quantitative RT-PCR analysis demonstrated significantly decreased mRNA expression of the GABA(A) receptor alpha1 subunit and of the enzyme GAD67 in FSs compared with SCs. There was also significantly increased mRNA expression of the AMPA receptor GluR2 and GluR3 subunits. mRNA levels of the immature cation chloride co-transporter NKCC1 were not detected in SCs or DCs but were present in FSs, while expression of the mature transporter, KCC2, was significantly decreased in FSs. Conclusions: This model of experimental FSs does not lead to spontaneous seizure generation but does lead to increased seizure susceptibility to kainic acid. This altered level of excitability is accompanied by decreased mRNA expression of GABA receptor subunits and GAD67, and increased glutamate receptor subunits. Expression of immature cation chloride co-transporters may also be contributing to altered levels of excitability. As the majority of patients with a FS do not develop epilepsy, but may have altered seizure susceptibility, this model may be a better reflection of the human condition and will be useful for further investigations of the long-term sequelae of these events.