title: Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.
abstract: BACKGROUND
  Reelin and GAD(67) expression is downregulated in cortical interneurons of schizophrenia (SZ) patients. This downregulation is probably mediated by epigenetic hypermethylation of the respective promoters caused by the selective increase of DNA-methyltransferase 1 in GABAergic neurons. Mice receiving methionine (MET) provide an epigenetic model for neuropathologies related to SZ. We studied whether MET-induced epigenetic reelin promoter hypermethylation and the associated behavioral alterations can be reduced by valproate in doses that inhibit histone deacetylases (HDACs).
  
  
  METHODS
  Mice treated with either methionine (MET) (5.2 mmol/kg/SC/twice daily) or valproate (1.5 mmol/kg/SC/twice daily) or MET+ valproate combination were tested for prepulse inhibition of startle (PPI) and social interaction (SI). S-adenosylmethionine, acetylated histone 3, reelin promoter methylation, and reelin mRNA were assayed in the frontal cortex.
  
  
  RESULTS
  Valproate enhances acetylated histone 3 content, and prevents MET-induced reelin promoter hypermethylation, reelin mRNA downregulation, and PPI and SI deficits. Imidazenil, a positive allosteric modulator at GABA(A) receptors containing alpha(5) subunits but inactive at receptors including alpha(1) subunits, normalizes MET-induced behavioral changes.
  
  
  CONCLUSIONS
  This MET-induced epigenetic mouse models the neurochemical and behavioral aspects of SZ that can be corrected by positively modulating the action of GABA at alpha(5)-containing GABA(A) receptors with imidazenil or by inhibiting HDACs with valproate, thus opening exciting new avenues for treatment of epigenetically modified chromatin in SZ morbidity.
authors.affiliation: Department of Psychiatry, Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Illinois 60612, USA.
authors.forename: Lucio
authors.initials: L
authors.lastname: Tremolizzo
authors.forename: Mohemed-Salim
authors.initials: MS
authors.lastname: Doueiri
authors.forename: Erbo
authors.initials: E
authors.lastname: Dong
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Grayson
authors.forename: John
authors.initials: J
authors.lastname: Davis
authors.forename: Graziano
authors.initials: G
authors.lastname: Pinna
authors.forename: Patricia
authors.initials: P
authors.lastname: Tueting
authors.forename: Virginia
authors.initials: V
authors.lastname: Rodriguez-Menendez
authors.forename: Erminio
authors.initials: E
authors.lastname: Costa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000374:Aggression / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001569:Benzodiazepines / Q000008:administration & dosage; D015153:Blotting, Western / Q000379:methods; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D018757:GABA Modulators / Q000008:administration & dosage; D006657:Histones / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage; D007150:Immunohistochemistry / Q000379:methods; D007398:Interpersonal Relations; D008297:Male; D008715:Methionine; D008745:Methylation / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D000091042:Reelin Protein; D013216:Reflex, Startle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: D000927:Anticonvulsants; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D018757:GABA Modulators; D006657:Histones; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; D001569:Benzodiazepines; D014635:Valproic Acid; D012436:S-Adenosylmethionine; C082661:imidazenil; D008715:Methionine; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases