Fluoxetine epigenetically alters the CaMKII promoter in nucleus accumbens to regulate δfosb binding and antidepressant effects

A. J. Robison, Vincent Vialou, Hao Sheng Sun, Benoit Labonte, Sam A Golden, Caroline Dias, Gustavo Turecki, Carol Tamminga, Scott Russo, Michelle Mazei-Robison, Eric J. Nestler

Research output: Contribution to journalArticle

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Abstract

Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor ΔFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that ΔFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that ΔFosB binds the CaMKII gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of ΔFosB to the CaMKII promoter and reduces CaMKII expression in NAc, despite the fact that ΔFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKII promoter, which blocks the ΔFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKII promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKII expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.

Original languageEnglish (US)
Pages (from-to)1178-1186
Number of pages9
JournalNeuropsychopharmacology
Volume39
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Fluoxetine
Nucleus Accumbens
Antidepressive Agents
Depression
Epigenomics
Phenotype
Chromatin Immunoprecipitation
Acetylation
Reward
Histones
Protein Kinases
Lysine
Chromatin
Transcription Factors

Keywords

  • accumbens
  • CaMKII
  • depression
  • DFosB
  • fluoxetine
  • histone

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Medicine(all)

Cite this

Robison, A. J., Vialou, V., Sun, H. S., Labonte, B., A Golden, S., Dias, C., ... Nestler, E. J. (2014). Fluoxetine epigenetically alters the CaMKII promoter in nucleus accumbens to regulate δfosb binding and antidepressant effects. Neuropsychopharmacology, 39(5), 1178-1186. https://doi.org/10.1038/npp.2013.319

Fluoxetine epigenetically alters the CaMKII promoter in nucleus accumbens to regulate δfosb binding and antidepressant effects. / Robison, A. J.; Vialou, Vincent; Sun, Hao Sheng; Labonte, Benoit; A Golden, Sam; Dias, Caroline; Turecki, Gustavo; Tamminga, Carol; Russo, Scott; Mazei-Robison, Michelle; Nestler, Eric J.

In: Neuropsychopharmacology, Vol. 39, No. 5, 2014, p. 1178-1186.

Research output: Contribution to journalArticle

Robison, AJ, Vialou, V, Sun, HS, Labonte, B, A Golden, S, Dias, C, Turecki, G, Tamminga, C, Russo, S, Mazei-Robison, M & Nestler, EJ 2014, 'Fluoxetine epigenetically alters the CaMKII promoter in nucleus accumbens to regulate δfosb binding and antidepressant effects', Neuropsychopharmacology, vol. 39, no. 5, pp. 1178-1186. https://doi.org/10.1038/npp.2013.319
Robison, A. J. ; Vialou, Vincent ; Sun, Hao Sheng ; Labonte, Benoit ; A Golden, Sam ; Dias, Caroline ; Turecki, Gustavo ; Tamminga, Carol ; Russo, Scott ; Mazei-Robison, Michelle ; Nestler, Eric J. / Fluoxetine epigenetically alters the CaMKII promoter in nucleus accumbens to regulate δfosb binding and antidepressant effects. In: Neuropsychopharmacology. 2014 ; Vol. 39, No. 5. pp. 1178-1186.
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