Absence epilepsy in rats : how nurture shapes nature : genotypic and environmental influences on spike-wave discharges across the lifespan

Abstract

Absence seizures are characterized by the spontaneous occurrence of 3 Hz generalized spike-wave discharges (SWD) in the electroencephalogram (EEG). Behaviorally seizures are accompanied by decreased consciousness and interruption of ongoing behavior. Although absence epilepsy has a genetic origin, evidence from an animal model (WAG/Rij rat) suggests that seizures are sensitive to environmental manipulations. In this thesis it is investigated in how far and in which way the genotype and the environment influence the phenotypic expression (SWD) of absence seizures. Four experiments are conducted in which various environmental manipulations (enriched/impoverished housing, neonatal handling/maternal deprivation) are applied across the life span in different rat strains (epileptic WAG/Rij, non-epileptic ACI). Measurements (EEG, behavior, neurophysiologic, and molecular biological analyses) are either performed around 3 or 6 months of age. The data reveal that the presence of SWD has a strong genetic component, but their various characteristics have different heritabilities. Next, all characteristics of SWD are sensitive to environmental influences throughout life, though they differ in their sensitivity. This possibly depends on the manipulation of the environment, its timing, or both, which suggests that environmental effects on SWD are rather complex and caused by a combination of factors. It is proposed that the environment influences SWD via various underlying seizure mediating mechanisms, for which a specific ion channel (Ih, HCN1) might be a possible candidate. Next to seizure related SWD, a second type of discharge (Type 2 SWD) is studied. The experiments show that both paroxysms are different phenomena, and that their phenotypic characteristics are controlled by distinct mechanisms. While the data suggest that the expression of Type 2 SWD, just like seizure related SWD, has an oligo- of polygenetic background, they seem to be mainly influenced by the environment, with the genotype playing a more indirect and mediating role.