Abstracts

WAG/Rij rats, a valid animal model of absence epilepsy, develop spontaneous 7-9 Hz spike-wave-discharges (SWD) in their EEG. Although SWD are mainly under genetic control, evidence from WAG/Rij rats shows that they are to some extent sensitive for environmental manipulations post-weaning. Here we study the influence of the neonatal rearing environment on SWD in adult WAG/Rij rats. Because recent observations link seizure activity in WAG/Rij rats to a reduction of the hyperpolarization activated cation current ([italic]I[/italic][sub]h[/sub]) in neurons of the somatosensory cortex, the site of seizure generation, we also investigated if possible alterations in seizure activity are correlated with changes in [italic]I[/italic][sub]h[/sub] and its channel subunits HCN1, 2 and 4. During postnatal days 1-21 WAG/Rij pups were neonatal handled (NH), maternal deprived (MD), or left undisturbed (control). In adulthood EEG and behavioral measurements were carried out to study early environmental influences on seizure activity. Furthermore, we performed whole-cell recordings from layer 5 pyramidal neurons, in situ hybridization and Western blot for HCN1, 2 and 4 subunits, at the somatosensory cortex. Rats that underwent NH or MD had less seizures compared to control rats. No differences were found for seizure duration or behavior. The seizure reduction was accompanied by a marked increase of [italic]I[/italic][sub]h[/sub] and HCN1 protein expression in neurons from the somatosensory cortex of NH and MD animals. The increase was specific to HCN1 protein expression and did not involve HCN2/4 protein expression, or mRNA expression of any of the subunits (HCN1,-2,-4). Our observations are the first evidence that changes in the neonatal environment have a long-term impact of absence seizures,[italic] I[/italic][sub]h[/sub] and HCN1. Our data suggest further that absence seizure reduction is associated with an increase of [italic]I[/italic][sub]h[/sub] and HCN1. Our findings shed new light on the role of[italic] I[/italic][sub]h[/sub] and HCN in brain development and its relation with absence epilepsy: it does show that genetically determined seizures are rather sensitive for environmental factors. (Supported by Dutch Organization for Scientific Research (NWO) Grant 425-20-401.)