Effects of neonatal MK-801 treatment on p70S6K-S6/eIF4B signal pathways and protein translation in the frontal cortex of the developing rat brain.

Abstract

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.

• Authors: Se Hyun Kim, Hong Geun Park, Han Soo Kim, Yong Min Ahn, Yong Sik Kim
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 13 Issue 9 Pg. 1233-46 (Oct 2010) ISSN: 1469-5111 [Electronic] England
• PMID: 20064280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Eukaryotic Initiation Factors
• Neuroprotective Agents
• eIF-4B
• Dizocilpine Maleate
• Protein Kinases
• Ribosomal Protein S6 Kinases, 70-kDa
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Animals, Newborn
• Dizocilpine Maleate (pharmacology)
• Dose-Response Relationship, Drug
• Eukaryotic Initiation Factors (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Frontal Lobe (drug effects, growth & development, metabolism)
• Neuroprotective Agents (pharmacology)
• Phosphorylation
• Prefrontal Cortex (drug effects, growth & development, metabolism)
• Protein Biosynthesis (drug effects)
• Protein Kinases (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction (drug effects)
• Time Factors