Abstracts

It is widely accepted that status epilepticus (SE) in early life does not result in major neuronal death as observed in adults. There is increasing evidence however that more subtle aspects of brain physiology are permanently affected. Of particular interest is the potential effect of repetitive early life seizures on the physiology of endogenous seizure controlling circuits, such as those involving the substantia nigra reticulata (SNR). The aim of the current study was to determine the effect of 3 episodes of SE, during early postnatal development, on the seizure controlling function of the SNR in rats., Three episodes of SE were induced in Sprague Dawely rat pups of both sexes on postnatal days 4 (P4), P5, and P6 by systemic injection of kainic acid ([KA] 1.25, 1.5, and 2mg/kg i.p. respectively). Animals were left until P28 when they were implanted with bilateral cannulae aimed at the anterior SNR. At P30, rats received bilateral infusions of the GABAA receptor agonist muscimol (100ng/0.25 [micro]l per side), which has been shown previously to have an anticonvulsant effect when infused into the anterior SNR at P30 (Veliskova & Moshé 2001). Control rats were infused with 0.25[micro]l/SNR of saline. Flurothyl seizure threshold for the first clonic seizure was determined 30 minutes later as the amount of flurothyl necessary to induce the seizure. Subsequently, cannulae placements were confirmed histologically. Only results from animals with cannulae placement in the anterior SNR are reported., Systemic injection of KA resulted in behavioral SE in all animals. Within 5 min of the injections, pups manifested scratching-like behavior and hindlimb clonic movements, hyperactivity, tonic or tonic clonic seizures followed by swimming-like movements intermixed with tonic or tonic clonic seizures. These seizures lasted for the entire observation period of 6 hrs. At P30 flurothyl thresholds were 179 [plusmn] 15.7[mu]l (saline n=4) and 169 [plusmn] 10.9[mu]l (muscimol n=7) in males, and 174 [plusmn] 25.9[mu]l (saline n=5) and 181 [plusmn] 15.7[mu]l (muscimol n=8) in females. There were no statistically significant differences between any of the groups (two way ANOVA, p [gt] 0.05, NS)., Repetitive episodes of SE during early postnatal development alter the GABAA receptor mediated seizure controlling function of the SNR. The results suggest that early life SE produces long-term alterations in the SNR GABAA receptor system, which leads to loss of the well-known anticonvulsant effects of GABAA receptor activation in the SNR of rats without prior seizures. Such alterations in seizure controlling circuits may predispose the brain to future seizures and epileptogenesis., (Supported by NIH NINDS grants NS 20253, NS 045243 and a grant from the Rett Syndrome Research Foundation.)