Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice

Biol Psychiatry. 2005 Mar 1;57(5):500-9. doi: 10.1016/j.biopsych.2004.11.046.

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.

Conclusion: 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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aggression / drug effects
  • Animals
  • Anticonvulsants / administration & dosage*
  • Behavior, Animal / drug effects*
  • Behavior, Animal / physiology
  • Benzodiazepines / administration & dosage
  • Blotting, Western / methods
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Chromosome Mapping / methods
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Epilepsy / drug therapy*
  • Epilepsy / etiology
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • GABA Modulators / administration & dosage
  • Histones / metabolism
  • Imidazoles / administration & dosage
  • Immunohistochemistry / methods
  • Interpersonal Relations
  • Male
  • Methionine
  • Methylation / drug effects
  • Mice
  • Motor Activity / drug effects
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Inhibition / drug effects
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Reflex, Startle / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • S-Adenosylmethionine / metabolism
  • Schizophrenia / chemically induced
  • Schizophrenia / complications
  • Schizophrenia / drug therapy*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Time Factors
  • Valproic Acid / administration & dosage*

Substances

  • Anticonvulsants
  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • GABA Modulators
  • Histones
  • Imidazoles
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Benzodiazepines
  • Valproic Acid
  • S-Adenosylmethionine
  • imidazenil
  • Methionine
  • Serine Endopeptidases
  • reelin protein