Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.
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.
Tremolizzo
Lucio
L
Department of Psychiatry, Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Illinois 60612, USA.
Doueiri
Mohemed-Salim
MS
Dong
Erbo
E
Grayson
Dennis R
DR
Davis
John
J
Pinna
Graziano
G
Tueting
Patricia
P
Rodriguez-Menendez
Virginia
V
Costa
Erminio
E
Guidotti
Alessandro
A
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*
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