EARLY-LIFE SEIZURES INDUCED BY GABAB–RECEPTOR ANTAGONIST INCREASE HIPPOCAMPAL KINDLING SUSCEPTIBILITY IN ADULT RATS

Objectives: The consequence of seizures in the developing brain is controversial in both animal and clinical studies. In a new model of early-life seizures, we induced seizures on postnatal day (PND) 15 using GABAB receptor antagonist CGP56999A. Since adult rats that had early-life CGP56999A-induced seizures showed decreased in inhibition in the hippocampus, we hypothesize that the rate of electrical kindling of the hippocampus is increased in these rats.

Methods: Seizure rats were given intraperitoneal (i.p.) CGP56999A 1–2mg/kg to induce seizures on PND 15 and control rats were given saline i.p. Convulsive seizures (5–10 times) were typically induced after CGP56999A injection. Starting on PND 50, hippocampal afterdischarges (ADs) were electrically evoked by a high-frequency stimulus train (1s train of 100Hz pulses) applied at an implanted electrode in hippocampal CA1 (stratum radiatum). ADs were repeated hourly, 5 times a day, until three stage 5 seizures were evoked. Two weeks after the last seizure, the rat was anesthetized with urethane and laminar field potentials were recorded in CA1 and dentate gyrus (DG), in response to paired-pulse stimulation of CA3 and medial perforant path.

Results: Adult rats that had early-life CGP56999A-induced seizures showed a significantly facilitated rate of hippocampal kindling compared to saline-injected controls (p<0.01); number of ADs to reach three stage 5 seizures was 20.7±1.8 and 47.0±8.4 for seizure and control rats, respectively. However, the primary AD duration at each seizure stage (1 to 5) did not differ between seizure and control rats. Rats that had CGP56999A-induced early-life seizures, but not control rats, showed a significant decrease in paired-pulse inhibition of the population spike evoked in CA1 (p<0.05) two weeks after kindling.

Conclusion: The result demonstrated that CGP56999A-induced early-life seizures exert a long-term effect on seizure susceptibility in the hippocampus, as shown by an increased rate of hippocampal kindling and loss of hippocampal inhibition in the adult rats. The CGP56999A model is easy to use in comparison to early-life kindling, or to status epilepticus models that induced much pathological damage. (supported by CIHR)