Abstracts

RATIONALE: Despite the prominent role of NMDA receptors in the pathogenesis of epilepsy, few studies have used NMDA as a convulsant in whole animals. Velisek and colleagues (Dev Brain Res 65:185, 1992; Epilepsia 40:1357, 1999) have shown that in developing rats, systemic NMDA induces seizures with a unique clinical phenotype ([dsquote]emprosthotonic[dsquote] or hyperflexion seizures) and electrographic pattern (electrodecrement). These features are not in kainic acid-induced seizures, suggesting that seizures activated by different glutamate receptors might cause different long-term consequences. Therefore, we investigated the effects of NMDA seizures during development on the susceptibility to seizures in adulthood. At the end of this activity, participants should be able to discuss how NMDA seizures during development alter seizure susceptibility in adulthood.
METHODS: Rat pups (P12-18) were injected with saline (n=36) or NMDA (n=64) at known convulsant doses (12-30 mg/kg, i.p.). Seizures were terminated 30 minutes later by ketamine (40 mg/kg, i.p.). On P90, rats were injected with pentylenetetrazol (PTZ, 50 mg/kg i.p.); latencies to and durations of seizure stages were recorded. Cresyl violet-stained sections of cortex and hippocampus were then examined for major cell loss or gliosis.
RESULTS: A characteristic sequence of seizure activity was seen after NMDA injection: initially rats became hyperactive with increased locomotor activity and agitation, followed by emprosthotonus, then generalized tonic/clonic activity. Ketamine terminated status epilepticus within minutes. At P90, there were significant differences in both the latency to class V PTZ seizures (con: 3.5[plusminus]0.3 min, NMDA: 1.3[plusminus]0.9 min; p=0.045) and their duration (con: 8.3[plusminus]0.6 min, NMDA: 11.2[plusminus]0.7 min; p=0.004). No obvious cell loss or gliosis was observed in either cerebral cortex or hippocampus.
CONCLUSIONS: NMDA causes a unique seizure phenotype in the developing brain. Despite the lack of overt cell loss following NMDA-induced status epilepticus early in life, treated rats show a marked increase in susceptibility to PTZ seizures in adulthood. This study provides additional evidence for long-term seizure-induced alteration of neuronal excitability.
[Supported by: Parents Against Childhood Epilepsy (P.A.C.E.) and The Charlie Foundation.]