Neonatal exposure to AY-9944 increases typical spike and wave discharges in WAG/Rij and Wistar rats

Abstract

Absence-epileptic seizures appear in the EEG as Spike and Wave Discharges (SWDs). Typical SWDs develop spontaneously in WAG/Rij rats, an inbred Wistar strain. Atypical SWDs however were reported in studies in which the cholesterol synthesis inhibitor AY-9944 was administered to neonatal Wistar rats, causing absence-like seizures later in life. Atypical SWDs seemed to differ from typical SWDs in 3 aspects: lower peak frequency, longer duration, and involvement of the hippocampus. The aim of the present study was to investigate the effect of AY-9944 on typical SWDs.Male Wistar and WAG/Rij rats were injected with 7.5 mg/kg AY-9944 or saline postnatally. After 6 months, EEGs were recorded from the cortex and the hippocampus. Incidence, duration and peak frequency of the SWDs were determined. The SWD stopping probability was estimated by hazard rate analysis. Hippocampal involvement was assessed by cross correlation analysis of the hippocampus and cortex channels.The Wistar rats unexpectedly showed a high incidence of spontaneous SWDs. The AY-treatment increased the total SWD duration in both Wistar and WAG/Rij rats: the incidence was 1.6 times higher and the mean SWD duration was 1.4 times longer than in the saline-treated rats. The peak frequency of the SWDs did not change. The hazard rates were lower in the AY-treated rats, so some very long SWDs were observed. Cross correlations of spiky activity in the hippocampus pointed to volume conduction rather than to genuine SWD activity in this area.In summary, we found no indication that SWDs in AY-treated animals differ from typical SWDs. However, since saline-treated rats had many spontaneous SWDs, other rat strains might respond differently. With respect to the mechanism, the appearance of long SWDs suggests that the SWD stopping mechanism is affected by the treatment. We speculate that this effect is due to changes in the distribution of GABA-ergic and glutamatergic receptors in lipid rafts.