LONG TERM EFFECTS OF SEIZURES ON THE DEVELOPING BRAIN

Children'S Hospital Boston, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Investigator's Abstract): Epilepsy is one of the most common, yet frightening, neurological disorders encountered in childhood. Of major concern is the cognitive and behavior deterioration seen in some children, particularly after prolonged seizures. There is now a considerable amount of data implicating excessive release of excitatory amino acids (EAA's), principally glutamate, as a cause for neuronal toxicity and a major effort is now being made to develop pharmacological agents that block EAA receptors. However, EAAs arc in learning, memory, and brain plasticity, raising concern about using these agents in the developing animal. Work from our laboratory has demonstrated that the long-term effects of prolonged seizures are age-dependent. Using kainic acid, pilocarpine, and continuous hippocampal stimulation we have demonstrated that prolonged seizures in rats below 20 days of age have substantially fewer behavioral abnormalities and no alteration in seizure susceptibility when compared to older animals. Furthermore, histological lesions can not be demonstrated in young animals despite seizures that are more severe than in older animals. If the immature brain is resistant to the long- term effects of prolonged seizures the question of whether EAA blockers should be administered is even more pertinent. To expand earlier observations we will determine if prolonged seizures in the immature brain are associated with physiological or morphological changes. Following induction of seizures using the pilocarpine or perforant pathway stimulation models in immature and mature rats we will examine hippocampal inhibition using evoked potentials and possible cell loss using cell counting techniques. To examine the physiological basis for this remarkable age-related effect, we will use microdialysis to measure glutamate and GABA release following during perforant pathway stimulation or pilocarpine administration. To examine the long-term effects of EAA receptor antagonists on the developing brain, we will administer NMDA and non- NMDA receptor antagonists to rats with prolonged seizures and age- matched controls. Outcome measures will include learning and memory as measured by the Morris water maze, seizure threshold using flurothyl inhalation, long term potentiation (LTP), a physiological model of learning in vivo, and histological analysis. Results of this study should provide additional insights into our understanding of the long- term consequences of seizures on the developing brain.