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.