TY - JOUR
T1 - NMDA-induced seizures in developing rats cause long-term learning impairment and increased seizure susceptibility
AU - Stafstrom, Carl E.
AU - Sasaki-Adams, Deanna M.
N1 - Funding Information:
This research was supported by Parents Against Childhood Epilepsy (P.A.C.E.) and the Brian J. Couto Research Fund.
PY - 2003/2
Y1 - 2003/2
N2 - 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.
AB - 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.
KW - Developing brain
KW - Emprosthotonus
KW - Epilepsy
KW - Infantile spasms
KW - NMDA
KW - Seizure
KW - Status epilepticus
KW - Water maze
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UR - http://www.scopus.com/inward/citedby.url?scp=12244287585&partnerID=8YFLogxK
U2 - 10.1016/S0920-1211(02)00258-9
DO - 10.1016/S0920-1211(02)00258-9
M3 - Article
C2 - 12576174
AN - SCOPUS:12244287585
SN - 0920-1211
VL - 53
SP - 129
EP - 137
JO - Epilepsy Research
JF - Epilepsy Research
IS - 1-2
ER -