Original articlesValproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice
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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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2022, NeuroscienceCitation Excerpt :A previous study in rat hippocampal neurons showed that depletion of protein arginine N-methyltransferase 3, which transfers a methyl group from SAM to specific proteins, causes deformation of dendritic spines (Miyata et al., 2010), suggesting the important roles of SAM-mediated methylation in spine maturation. In contrast, studies in mice have shown that protracted administration of L-methionine, a precursor of SAM, increases SAM levels, hypermethylates and downregulates certain genes, and decreases dendritic spine density in the pyramidal neurons of the frontal cortex (Tremolizzo et al., 2005; Dong et al., 2007; Tueting et al., 2010). These findings suggest that both SAM excess and deficiency may inhibit maturation of neuronal dendrites.
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