Effects of neonatal MK-801 treatment on p70S6K-S6/eIF4B signal pathways and protein translation in the frontal cortex of the developing rat brain.
Systemic injections of MK-801, a selective NMDAR antagonist, into neonatal rats induces long-term neurochemical and behavioural changes. It has been suggested that these changes form the neurodevelopmental basis for schizophrenia-like behaviour in rats. In this study, 7-d-old rats were treated with MK-801, and their frontal cortices were examined to investigate the effects on p70S6K-S6 signal pathway and on protein translation, which play crucial roles in the neurodevelopmental process. MK-801, in doses of 0.5 and 1.0 mg/kg, induced a decrease in phosphorylation of p70S6K and its substrates, S6 and eIF4B, in the first 8 h, and no change at 24 and 48 h. These effects were more prominent after two injections of MK-801 than one. Decreased S6 phosphorylation by MK-801 was evident in the prefrontal, cingulate, and insular cortex. In two representative upstream p70S6K-S6 pathways related to ERK1/2 and Akt, changes in ERK1/2-p90RSK phosphorylation were accompanied by changes of p70S6K-S6. Although two MK-801 injections induced a dose-dependent decrease in phosphorylation of Akt and mTOR at 4 and 8 h, a single injection did not produce a significant effect. Protein synthesis rate, measured by [3H]leucine incorporation in frontal cortical tissue, was reduced until 24 h after two MK-801 (1.0 mg/kg) injections. In summary, this study found that neonatal MK-801 treatment induced dysregulation in the p70S6K-S6/eIF4B pathway and protein translation in the frontal cortex of the developing rat brain, which may suggest an important role of protein translation machinery in the MK-801 neurodevelopmental animal model of schizophrenia.
Kim
Se Hyun
SH
Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Seoul, Republic of Korea.
Park
Hong Geun
HG
Kim
Han Soo
HS
Ahn
Yong Min
YM
Kim
Yong Sik
YS
D000818:Animals; D000831:Animals, Newborn; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D039642:Eukaryotic Initiation Factors; D018696:Neuroprotective Agents; C031799:eIF-4B; D016291:Dizocilpine Maleate; D011494:Protein Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases