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

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.

• Authors: Carl E Stafstrom, Deanna M Sasaki-Adams
• Journal: Epilepsy research (Epilepsy Res) Vol. 53 Issue 1-2 Pg. 129-37 (Feb 2003) ISSN: 0920-1211 [Print] Netherlands
• PMID: 12576174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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