Dysregulation of Epigenetic Control Contributes to Schizophrenia-Like Behavior in Ebp1+/- Mice.

Inwoo Hwang,Jee-Yin Ahn

doi:10.3390/ijms21072609

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.

Highlights

The ErbB3-binding protein 1 (EBP1)-related gene Ebp1 (Pa2g4) is comprised of 10 exons and encodes two alternatively spliced EBP1 isoforms, p48 and p42 [1]
The mice demonstrated abnormal behaviors including damaged responses to introduction of social novelty, higher levels of anxiety, impaired marble-burying behavior, and other cognitive dysfunctions. These unusual behaviors support the possibility that EBP1 deficient mutant mice presented SZ-like behaviors similar to those observed in SZ models from the previous reports
We found that heterozygous EBP1-deletion 1 mutant mice exhibited developmental abnormalities in hippocampus, especially in neurons located in Stratum Oriens (SO) of CA3/2 region

Summary

Introduction

The ErbB3-binding protein 1 (EBP1)-related gene Ebp (Pa2g4) (chromosome 12q13.2 in humans; chromosome 10 D3 in mouse) is comprised of 10 exons and encodes two alternatively spliced EBP1 isoforms, p48 and p42 [1]. The primary structure of two isoproteins, p48 (1-394 amino acids) and p42(55-394 amino acids), is different. Isoprotein p42 is missing 54 amino acids at its N-terminus. EBP1 isoforms have distinct functions and participate in various cellular processes. Whereas p42 EBP1, known as a binding partner of ERBB3 [5], can inhibit PI3K activity via p85-subunit degradation and recruitment of the E3 ligase and HSP70/CHIP complexes [6,7]. Despite distinctive cellular functions of two EBP1 isoforms during early embryonic development, only p48 EBP1 is detectable at both RNA and protein levels throughout the entire organism including brain tissues. The physiological function of p48 EBP1 were not defined in developing brain tissues in vivo, because mammalian models of EBP1 deletion have not been developed

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