NMDA-induced seizures in developing rats cause long-term learning impairment and increased seizure susceptibility

Epilepsy Res. 2003 Feb;53(1-2):129-37. doi: 10.1016/s0920-1211(02)00258-9.

Abstract

N-methyl-D-aspartate (NMDA) receptors play a prominent role in the pathogenesis of epilepsy, yet few studies have used NMDA as a convulsant in whole animals. In developing rats, systemic NMDA induces seizures with a unique seizure phenotype ("emprosthotonic" or hyperflexion seizures) and electrographic pattern (electrodecrement). These features are not seen in kainic acid-induced seizures, suggesting that seizures activated by NMDA might cause different long-term consequences. Therefore, we investigated the effects of NMDA seizures during development on cognitive function and susceptibility to seizures in adulthood. Rat pups (P12-20) were injected with saline (n=36) or NMDA (n=64) at convulsant doses (15-30mg/kg, i.p.). After NMDA injection, a characteristic sequence of seizure activity was seen: initial behavioral arrest, followed by hyperactivity, agitation, and then emprosthotonus and generalized tonic-clonic seizures. Seizures were terminated 30min later by ketamine (50mg/kg, i.p.). On P85, rats underwent behavioral testing in the water maze. Rats that had experienced NMDA seizures as pups took significantly longer to learn the platform location over 5 days of testing, compared to controls. On P90, rats were injected with pentylenetetrazol (PTZ, 50mg/kg, i.p.) to assess their susceptibility to generalized seizures. NMDA-treated rats had decreased latency and increased duration of class V PTZ seizures. Cresyl violet-stained sections of cortex and hippocampus had no obvious cell loss or gliosis. In summary, NMDA causes a unique seizure phenotype in the developing brain, with subsequent deficits in spatial learning and an increased susceptibility to PTZ seizures in adulthood. This study provides additional evidence for long-term alterations of neuronal excitability and cognitive capacity associated with seizures during development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain / pathology
  • Cognition Disorders / chemically induced
  • Cognition Disorders / psychology
  • Convulsants
  • Electroencephalography
  • Excitatory Amino Acid Agonists / toxicity*
  • Learning Disabilities / chemically induced*
  • Learning Disabilities / psychology*
  • Maze Learning / drug effects
  • N-Methylaspartate / toxicity*
  • Neurons / pathology
  • Pentylenetetrazole
  • Phenotype
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / chemically induced*
  • Seizures / psychology*
  • Status Epilepticus / chemically induced
  • Status Epilepticus / psychology

Substances

  • Convulsants
  • Excitatory Amino Acid Agonists
  • N-Methylaspartate
  • Pentylenetetrazole