Elsevier

Biological Psychiatry

Volume 57, Issue 5, 1 March 2005, Pages 500-509
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2004.11.046Get rights and content

Background

Reelin and GAD67 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 GABAA receptors containing α5 subunits but inactive at receptors including α1 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 α5-containing GABAA receptors with imidazenil or by inhibiting HDACs with valproate, thus opening exciting new avenues for treatment of epigenetically modified chromatin in SZ morbidity.

Section snippets

Animals and drug administration schedule

B6C3Fe male mice (60–80 days old) received SC vehicle (VEH; 10 mL/kg saline), L-methionine (MET; 5.2 mmol/kg), or valproate ([VPA] 1.5 mmol/kg), or a combination of the two drugs [MET+VPA] twice daily for 15 days. Unless otherwise indicated, mice were left untreated for 16–20 hours before neurochemical or behavioral measurements. Imidazenil, 3.3 μmol/kg was administered SC 60 min before the PPI test and 120 min before the social interaction test. Doses and schedule of administration were

Histone 3 (H3)-acetylation

Valproate (1.5 mmol/kg SC) administered to mice treated for 15 days with VEH induced within 2 hours a three-fold increase of acetylated H3 in FC (Figure 1). In mice that received protracted treatment with VPA, the injection of VPA (1.5 mmol/kg) induced within 2 hours an increase of hyperacetylated H3-like immunoreactivity in the FC that was similar to that of VEH-treated mice (Figure 1). This increase of acetylated H3 was completely gone 12 hours after the VPA injection (Figure 1).

We also found

MET as a tool to investigate epigenetic regulation of reelin promoter hypermethylation

Methionine, administered to mice in doses that increase FC content of the methyl donor SAM, elicits reelin promoter hypermethylation and the subsequent downregulation of the expression of the reelin gene by an extent (∼ 50%) that is comparable to the reelin defect detected in the prefrontal cortex (PFC) of schizophrenia patients (Guidotti et al 2000). The analysis of single CpG dinucleotide methylation in the mouse reelin promoter region comprising −340 and +160 bp indicates that after MET

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