An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability.
Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this down-regulation. Protracted l-methionine (6.6 mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice. This effect of l-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulsestartle interval increased in mice receiving l-methionine. Valproic acid (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk.
Tremolizzo
L
L
Department of Psychiatry, Psychiatric Institute, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
Carboni
G
G
Ruzicka
W B
WB
Mitchell
C P
CP
Sugaya
I
I
Tueting
P
P
Sharma
R
R
Grayson
D R
DR
Costa
E
E
Guidotti
A
A
D000107:Acetylation; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics*; D008715:Methionine / Q000494:pharmacology; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D000091042:Reelin Protein; D013216:Reflex, Startle; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics; D012697:Serine Endopeptidases; D014635:Valproic Acid / Q000494:pharmacology
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D006657:Histones; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; D014635:Valproic Acid; D008715:Methionine; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1