Dysregulation of epigenetic control contributes to schizophrenia-like behavior in Ebp1+/- mice

Abstract

Dysregulation of epigenetic machinery can cause a variety of neurological disorders associated with cognitive abnormalities. In the hippocampus of postmortem Schizophrenia (SZ) patients, the most notable finding is the deregulation of GAD67 along with differential regulation of epigenetic factors associated with glutamate decarboxylase 67 (GAD67) expression. As we previously reported, ErbB3-binding protein 1 (EBP1) is a potent epigenetic regulator. EBP1 can induce repression of Dnmt1, a well-studied transcriptional repressor of GAD67. In this study, we investigated whether EBP1 contributes to the regulation of GAD67 expression in the hippocampus, controlling epigenetic machinery. In accordance with SZ-like behaviors in Ebp1(+/-) mice, heterozygous deletion of EBP1 led to a dramatic reduction of GAD67 expression, reflecting an abnormally high level of Dnmt1. Moreover, we found that EBP1 binds to the promoter region of HDAC1, which leads to histone deacetylation of GAD67, and suppresses histone deacetylase 1 (HDAC1) expression, inversely mirroring an unusually high level of HDAC1 in Ebp1(+/-) mice. However, EBP1 mutant (p.Glu 183 Ter) found in SZ patients did not elevate the expression of GAD67, failing to suppress Dnmt1 and/or HDAC1 expression. Therefore, this data supports the hypothesis that a reduced amount of EBP1 may contribute to an etiology of SZ due to a loss of transcriptional inhibition of epigenetic repressors, leading to a decreased expression of GAD67.