Long-term behavioural, molecular and morphological effects of neonatal NMDA receptor antagonism.
Brief N-methyl-D-aspartate (NMDA) receptor blockade in neonatal rats has been reported to increase neuronal apoptosis. We replicated this finding using MK-801 (0.5 mg/kg) administered twice on postnatal day 7, and then studied the long-term consequences. In adulthood, treated rats showed reduced volume and neuronal number within the hippocampus, and altered hippocampal NMDA receptor (NR1 subunit) expression. Synaptophysin mRNA was decreased in the thalamus (laterodorsal nucleus). Adult MK-801-treated females had prepulse inhibition deficits and increased locomotor activity. The data show that a transient and limited glutamatergic intervention during development can have chronic behavioural, structural and molecular effects. The effects are reminiscent of alterations reported in schizophrenia and, as such, are consistent with hypotheses advocating a role for NMDA receptor hypofunction, and aberrant apoptosis, in the neurodevelopmental pathogenesis of the disorder.
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002452:Cell Count; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006624:Hippocampus / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007266:Inhibition, Psychological; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D012737:Sex Factors; D016708:Synaptophysin / Q000235:genetics; D013788:Thalamus / Q000254:growth & development / Q000378:metabolism; D013995:Time
D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; D016291:Dizocilpine Maleate