Neuronal Activity, TGFβ-Signaling and Unpredictable Chronic Stress Modulate Transcription of Gadd45 Family Members and DNA Methylation in the Hippocampus

Abstract

Neuronal activity is altered in several neurological and psychiatric diseases. Upon depolarization not only neurotransmitters are released but also cytokines and other activators of signaling cascades. Unraveling their complex implication in transcriptional control in receiving cells will contribute to understand specific central nervous system (CNS) pathologies and will be of therapeutically interest. In this study we depolarized mature hippocampal neurons in vitro using KCl and revealed increased release not only of brain-derived neurotrophic factor (BDNF) but also of transforming growth factor beta (TGFB). Neuronal activity together with BDNF and TGFB controls transcription of DNA modifying enzymes specifically members of the DNA-damage-inducible (Gadd) family, Gadd45a, Gadd45b, and Gadd45g. MeDIP followed by massive parallel sequencing and transcriptome analyses revealed less DNA methylation upon KCl treatment. Psychiatric disorder-related genes, namely Tshz1, Foxn3, Jarid2, Per1, Map3k5, and Arc are transcriptionally activated and demethylated upon neuronal activation. To analyze whether misexpression of Gadd45 family members are associated with psychiatric diseases, we applied unpredictable chronic mild stress (UCMS) as established model for depression to mice. UCMS led to reduced expression of Gadd45 family members. Taken together, our data demonstrate that Gadd45 family members are new putative targets for UCMS treatments.

Perinatal exposure to the SSRI paroxetine alters the methylome landscape of the developing dentate gyrus

“…Studies in humans found an association between certain FOXN3 polymorphisms and suicidal attempts (Galfalvy et al., ; Sokolowski, Wasserman, & Wasserman, ) and increased FOXN3 levels in the PFC of suicide victims (Le‐Niculescu et al., ; Zhurov et al., ). A recent study in a mouse model of depression found decreased Foxn3 expression in the adult hippocampus (Grassi et al., ). Foxn3 expression is activity dependent and undergoes demethylation, resulting in increased expression (Grassi et al., ), suggesting paroxetine‐induced changes in dendritic spine formation and mitochondrial trafficking to the dendrites may be upstream of changes in Foxn3 expression.…”

“…A recent study in a mouse model of depression found decreased Foxn3 expression in the adult hippocampus (Grassi et al., ). Foxn3 expression is activity dependent and undergoes demethylation, resulting in increased expression (Grassi et al., ), suggesting paroxetine‐induced changes in dendritic spine formation and mitochondrial trafficking to the dendrites may be upstream of changes in Foxn3 expression.…”

Sequence Analysis of Drug Target Genes with Suicidal Behavior in Bipolar Disorder Patients

“…Together with BDNF, TGFB may regulate DNA methylation in the hippocampus [35]. SB-431542 is a small-molecular inhibitor of TGFBR1 developed by GSK; it has been investigated for antitumor activities, though the effects of this molecule on mood and behavior will need to be explored in preclinical models [36].…”

The Role of Activity-Dependent DNA Demethylation in the Adult Brain and in Neurological Disorders

“…However, reduced occupancy of GADD45B on the Bdnf IX promoter was found, which is in line with reduced Bdnf IX expression (Gavin et al, 2012 ). Recently, GADD45B expression was shown to be regulated by transforming growth factor beta (TGFB) signaling and protein levels of GADD45B are reduced in a model of chronic mild stress (Grassi et al, 2017 ). Moreover, a reduction in expression levels of the immediate early gene Arc was also associated with reduced levels of GADD45B and DNA demethylation in this stress model (Grassi et al, 2017 ).…”