Abstracts

The effects repeated seizures have on the developing brain have long been debated. Studies reported here examined the long term effects of seizures in infant rats by a unilateral intrahippocampal injection of tetanus toxin on postnatal day 10.
Video-EEG recordings were conducted between postnatal day 50 and 60. Alterations in seizure susceptibility were assayed on day 22 or 50 using the flurothyl method. Changes in selected pre and postsynaptic markers for GABAergic synapses were also determined by quantitative immunoblotting on day 50.
Behavioral seizures were first observed on day 12. Seizures gradually declined in frequency over the next 5 days and were not observed after day 17. On average, rats had 8.4 [plusmn] 2.7 seizures during 10 daily 1 hour behavioral monitoring sessions. As adults (days 50-60), all rats displayed interictal spikes in the hippocampus and/or overlying cortex. Brief (2-5 sec) electrographic seizures without behavioral accompaniments were recorded in only one of five animals. Since rats did not display spontaneous behavioral seizures, flurothyl was used to assay changes in seizure susceptibility. When rats were tested on day 50, they had a small (15%) but significant decrease in the time to onset of seizures when compared to litter mate controls. However, when another group of rats was tested on day 22, a marked increase in seizure susceptibility was observed. Thus rats appear to progress from a period of overt spontaneous seizures (day 12-17), through a period of marked seizure susceptibility (day 22) to one of lessened seizure susceptibility (day 50). The hypothesis was put forward that alterations in seizure susceptibility reflect a gradual recovery of the brain to a normal state. To address this, pre and postsynaptic markers for GABAergic neurotransmission were assayed. Contrary to our hypothesis, results showed that the expression levels of GAD67 and the alpha1 subunit of the GABAa receptor were actually increased. These changes were observed on both the CA3 and CA1 subfields but not in the dentate gyrus. The expression levels of the beta 2-3 and gamma 2 subunits of the GABAa receptor were unchanged.
The hippocampus appears to compensate for early-life seizures and possibly persistent interictal activity by increasing the expression of GAD67, the GABA synthetic enzyme, and at least one GABAa receptor subunit. Such compensatory changes could contribute to the progressive diminution in seizure susceptibility observed.
[Supported by: NIH, NINDS Grants NS18309 and NS37171.]