Molecular Neurobiology

, Volume 56, Issue 12, pp 8537–8556 | Cite as

Stress-Induced Epigenetic Changes in Hippocampal Mkp-1 Promote Persistent Depressive Behaviors

  • Jung-Eun Lee
  • Hye-Jin Kwon
  • Juli Choi
  • Pyung-Lim HanEmail author


Chronic stress induces persistent depressive behaviors. Stress-induced transcriptional alteration over the homeostatic range in stress hormone–sensitive brain regions is believed to underlie long-lasting depressive behaviors. However, the detailed mechanisms by which chronic stress causes those adaptive changes are not clearly understood. In the present study, we investigated whether epigenetic changes regulate stress-induced depressive behaviors. We found that chronic stress in mice downregulates the epigenetic factors HDAC2 and SUV39H1 in the hippocampus. A series of follow-up analyses including ChIP assay and siRNA-mediated functional analyses reveal that glucocorticoids released by stress cumulatively increase Mkp-1 expression in the hippocampus, and increased Mkp-1 then debilitates p-CREB and PPARγ, which in turn suppress the epigenetic factors HDAC2 and SUV39H1. Furthermore, HDAC2 and SUV39H1 normally suppress the transcription of the Mkp-1, and therefore the reduced expression of HDAC2 and SUV39H1 increases Mkp-1 expression. Accordingly, repeated stress progressively strengthens a vicious cycle of the Mkp-1 signaling cascade that facilitates depressive behaviors. These results suggest that the hippocampal stress adaptation system comprising HDAC2/SUV39H1-regulated Mkp-1 signaling network determines the vulnerability to chronic stress and the maintenance of depressive behaviors.


Stress adaptation Epigenetic factors HDAC2 SUV39H1 Mkp-1 



Ca2+/calmodulin-dependent protein kinase II alpha


CREB-binding protein


Chromatin immunoprecipitation


cAMP response element binding protein


Extracellular signal-regulated kinase




Glucocorticoid receptor




Histone acetyltransferase


Histone deacetylase


Histone deacetylase 2


c-Jun N-terminal kinase


Mitogen-activated protein kinase


Mitogen-activated protein kinase phosphatase-1


p38 mitogen-activated protein kinase


Peroxisome proliferator-activated receptor gamma


Rosmarinic acid


Reverse transcription polymerase chain reaction


Suppressor of variegation 3–9 homolog 1


Vitamin C


Funding Information

This research was supported by a grant (2018R1A2B2001535) from the Ministry of Science, ICT and Future Planning, Republic of Korea.

Compliance with Ethical Standards

Competing Interests

The authors declare no competing financial interests.


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Authors and Affiliations

  1. 1.Department of Brain and Cognitive SciencesEwha Womans UniversitySeoulRepublic of Korea
  2. 2.Department of Chemistry and Nano ScienceEwha Womans UniversitySeoulRepublic of Korea
  3. 3.Brain Disease Research InstituteEwha Womans UniversitySeoulRepublic of Korea

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