Gadd45b mediates depressive-like role through DNA demethylation

Abstract

Animal studies using chronic social defeat stress (CSDS) in mice showed that brain-derived neurotrophic factor (BDNF) signaling in the mesolimbic dopamine (DA) circuit is important for the development of social aversion. However, the downstream molecular targets after BDNF release from ventral tegmental area (VTA) DA terminals are unknown. Here, we show that depressive-like behaviors induced by CSDS are mediated in part by Gadd45b downstream of BDNF signaling in the nucleus accumbens (NAc). We show that Gadd45b mRNA levels are increased in susceptible but not resilient mice. Intra-NAc infusion of BDNF or optical stimulation of VTA DA terminals in NAc enhanced Gadd45b expression levels in the NAc. Importantly, Gadd45b downregulation reversed social avoidance in susceptible mice. Together, these data suggest that Gadd45b in NAc contributes to susceptibility to social stress. In addition, we investigated the function of Gadd45b in demethylating CpG islands of representative gene targets, which have been associated with a depressive phenotype in humans and animal models. We found that Gadd45b downregulation changes DNA methylation levels in a phenotype-, gene-, and locus-specific fashion. Together, these results highlight the contribution of Gadd45b and changes in DNA methylation in mediating the effects of social stress in the mesolimbic DA circuit.

Regulation of dopamine-dependent transcription and cocaine action byGadd45b

“…Despite the overall increase in protein, GADD45B binding is decreased at the BDNF promoter in patients with psychosis, corresponding to increased 5mC and 5hmC levels. In a rodent model of depression, Gadd45b expression was upregulated in the NAc of stress-susceptible mice following a chronic social defeat stress (CSDS) behavioral paradigm [22]. These increases in Gadd45b were not observed in stress-resilient mice, and downregulation of striatal Gadd45b rescued the social avoidance phenotype that distinguishes susceptible animals in CSDS.…”

“…Gadd45b has also been shown to act as an IEG in other brain regions. For instance, increases in Gadd45b mRNA are observed in the NAc after both optical stimulation of VTA DA neuron terminals in the NAc and following direct infusion of brain-derived neurotrophic factor (BDNF) into the NAc [22]. Here, we demonstrate that Gadd45b acts as an IEG in the ventral striatum following cocaine administration in vivo (Figure 1b,f) and DRD1 activation in vitro (Figure 3c-e), and we show for the first time that striatal induction of Gadd45b is dependent on both MAPK and CREB signaling (Figure 3gh).…”

“…In human post-mortem cortical tissue, decreased GADD45B binding to the BDNF promoter was associated with higher levels of 5mC and 5hmC [48]. In the mouse NAc, downregulation of Gadd45b alters DNA methylation in a phenotype-, gene-, and locus-specific way, potentially underlying susceptibility or resilience to stress [22]. Despite evidence suggesting that Gadd45b is important in activity-dependent DNA demethylation, it is still unclear how the GADD45B protein is involved in this process.…”

“…Previous studies have characterized the role of ten-eleven translocation (TET) enzymes in the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and additional oxidation that results in base excision and replacement [18][19][20]. In the brain, Gadd45b, a member of the Growth arrest and DNA-damage-inducible gene family, is associated with decreased CpG methylation in gene regulatory regions and is a critical for activity-dependent DNA demethylation, potentially working in concert with TET and thymine-dependent glycosylase proteins [18,[21][22][23][24]. Moreover, Gadd45b is upregulated in response to neuronal activity in multiple brain regions and plays a key role in experience-dependent learning [21,22,25,26].…”

“…In the brain, Gadd45b, a member of the Growth arrest and DNA-damage-inducible gene family, is associated with decreased CpG methylation in gene regulatory regions and is a critical for activity-dependent DNA demethylation, potentially working in concert with TET and thymine-dependent glycosylase proteins [18,[21][22][23][24]. Moreover, Gadd45b is upregulated in response to neuronal activity in multiple brain regions and plays a key role in experience-dependent learning [21,22,25,26]. These results demonstrate that Gadd45b may link experiencedependent neuronal activity and downstream regulation of DNA methylation states.…”