title: MK-801, a NMDA receptor antagonist, increases phosphorylation of histone H3 in the rat medial prefrontal cortex.
abstract: BACKGROUND
  The present study investigated whether MK-801, when given in doses that cause psychomimetic effects in rats, could alter the phosphorylation of histone 3 (H3) at serine 10 (H3S10p) and the acetylation of H3 at lysine 14 (H3K14ac) in the medial prefrontal cortex (mPFC). These posttranslational modifications of H3 promote chromatin relaxation and increase the probability of gene expression.
  
  
  METHODS
  Stereological counting, immunoblot analysis and confocal laser scanning microscopy.
  
  
  RESULTS
  Treatment with MK-801 (0.4 mg/kg) evoked a time-dependent increase in the number of H3S10p positive nuclei in both the II/III and V/VI layers of the mPFC, reaching the peak of activation 30 min after injection. MK-801 treatment (0.4 mg/kg) failed to alter H3K14ac. These effects were confirmed by immunoblot analysis on tissue samples from the mPFC. Analysis of cortical cells expressing H3S10p positive nuclei revealed that constitutive and MK-801-induced expression of H3S10p was observed only in neurons and not in glia cells (H3S10p colocalized with NeuN but not with S-100β). Moreover, it has been found that H3S10p is exclusively present in pyramidal (glutamate-positive) but not in cortical GABA-ergic interneurons (GABA-positive). The effects of MK-801 can be attenuated or blocked by the neuroleptic drug risperidone. In the cortical layer II/III, risperidone was effective at doses of 0.2 and 1 mg/kg, while it was only active at a dose of 1 mg/kg in the V/VI layer. Again, these stereological data were confirmed by immunoblot analysis.
  
  
  CONCLUSIONS
  Our results indicate that MK-801 may increase the transcriptional activity of mPFC via the activation of the epigenetic program associated with H3S10p phosphorylation during the course of experimental psychosis.
authors.affiliation: Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. nfwedzon@cyf-kr.edu.pl.
authors.forename: Marzena
authors.initials: M
authors.lastname: Maćkowiak
authors.forename: Rafał
authors.initials: R
authors.lastname: Guzik
authors.forename: Dorota
authors.initials: D
authors.lastname: Dudys
authors.forename: Ewelina
authors.initials: E
authors.lastname: Bator
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Wędzony
mesh_terms: D000107:Acetylation; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D008239:Lysine; D008297:Male; D010641:Phenotype; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011605:Psychoses, Substance-Induced / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D012694:Serine; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D006657:Histones; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016291:Dizocilpine Maleate; D008239:Lysine; D018967:Risperidone