Prenatal MAM administration affects histone H3 methylation in postnatal life in the rat medial prefrontal cortex.

Several findings have indicated that schizophrenia may be connected with the impaired epigenetic regulation of gene transcription. The present study investigated the epigenetic modifications connected with histone H3 methylation at lysine (K)4 and K9 in the medial prefrontal cortex (mPFC) in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17, which impairs the sensorimotor gating process in adult but not adolescent animals. The effect of MAM was determined at different postnatal ages, pre-puberty (P15, P30 and P45) and post-puberty (P60 and P70), using western blot analyses. MAM treatment altered the levels of H3K9me2 before puberty. H3K9me2 was decreased at P15 and P45 but was increased at P30. In contrast, H3K4me3 was noticeably decreased in adult rats. Immunofluorescence experiments revealed that H3K9me2 protein levels were increased in neuronal cells at P30 and that H3K4me3 levels were decreased in astrocytes at P60 after MAM administration. Decreases in the methyltransferase ASH2L protein levels at P45, P60 and P70 were also observed, while the protein levels of the methyltransferase G9a did not change. In addition, levels of the demethylases LSD1 and JARID1c were analysed after MAM administration. LSD1 protein levels were increased at P15 but decreased at P30. JARID1c protein levels were increased in the MAM-treated animals at P60. Decreased Gad1 mRNA levels were found in adult MAM-treated animals, similar to alternation observed in schizophrenia. The present study indicates that prenatal MAM administration evokes changes in the methylation patterns of histone H3 during postnatal life.