title: 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.affiliation: Department of Neurology, Neuroscience Training Program, H6-528, University of Wisconsin, 600 Highland Avenue, 53792, Madison, WI, USA. stafstrom@neurology.wisc.edu
authors.forename: Carl E
authors.initials: CE
authors.lastname: Stafstrom
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Sasaki-Adams
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000139:chemically induced / Q000523:psychology; D003292:Convulsants; D004569:Electroencephalography; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007859:Learning Disabilities / Q000139:chemically induced* / Q000523:psychology*; D018782:Maze Learning / Q000187:drug effects; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000473:pathology; D010433:Pentylenetetrazole; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000523:psychology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000523:psychology
chemical_list: D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D010433:Pentylenetetrazole