Fluoxetine epigenetically alters the CaMKII? promoter in nucleus accumbens to regulate ?FosB binding and antidepressant effects
Language: 
English
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 ?FosB 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 ?FosB 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 ?FosB 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 ?FosB to the CaMKII? promoter and reduces CaMKII expression in NAc, despite the fact that ?FosB 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 ?FosB 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.

Author(s): 
Robison, A. J.
Vialou, Vincent
Sun, Hao-Sheng
LabontÈ, Benoit
Golden, Sam A.
Dias, Caroline
Turecki, Gustavo
Tamminga, Carol
Russo, Scott
Mazei-Robison, Michelle
Nestler, Eric J.
Item Type: 
Journal Article
Publication Title: 
Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Journal Abbreviation: 
Neuropsychopharmacology
Publication Date: 
2014-04
Publication Year: 
2014
Pages: 
1178-1186
Volume: 
39
Issue: 
5
ISSN: 
1740-634X
DOI: 
10.1038/npp.2013.319
Library Catalog: 
PubMed
Extra: 
PMID: 24240473 PMCID: PMC3957112

Turabian/Chicago Citation

A. J. Robison, Vincent Vialou, Hao-Sheng Sun, Benoit LabontÈ, Sam A. Golden, Caroline Dias, Gustavo Turecki, Carol Tamminga, Scott Russo, Michelle Mazei-Robison and Eric J. Nestler. 2014-04. "Fluoxetine epigenetically alters the CaMKII? promoter in nucleus accumbens to regulate ?FosB binding and antidepressant effects." Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 39: 5: 1178-1186. 10.1038/npp.2013.319.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1038/npp.2013.319 | issn = 1740-634X | volume = 39 | pages = 1178-1186 | last = Robison | first = A. J. | coauthors = Vialou, Vincent, Sun, Hao-Sheng, LabontÈ, Benoit, Golden, Sam A., Dias, Caroline, Turecki, Gustavo, Tamminga, Carol, Russo, Scott, Mazei-Robison, Michelle, Nestler, Eric J. | title = Fluoxetine epigenetically alters the CaMKII? promoter in nucleus accumbens to regulate ?FosB binding and antidepressant effects | journal = Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology | date = 2014-04 | pmid = | pmc = }} </ref>