title: Retinoid x receptor gamma is implicated in docosahexaenoic acid modulation of despair behaviors and working memory in mice.
abstract: BACKGROUND
  Omega-3 polyunsaturated fatty acids, including docosahexaenoic acid (DHA), have antidepressant and promnemonic functions. The mechanisms of such activities are still elusive and may involve retinoid X receptors (RXRs), transcription factors known to bind DHA in vitro.
  
  
  METHODS
  Promnemonic and antidespair activities of acute DHA treatment were tested in BALBcByJ mice using spontaneous alternation and forced swim test, respectively. The involvement of retinoid receptors in such DHA activities was investigated using RXR and/or retinoic acid receptor (RAR) agonists to mimic DHA activities or a synthetic pan-RXR antagonist to block them. Involvement of RXR isotypes was analyzed using the same tasks and delayed nonmatch to place for working memory in RXRγ knockout mice.
  
  
  RESULTS
  Docosahexaenoic acid decreased despair behavior and improved working memory in BALBcByJ mice. Such effects were suppressed by co-treatment with BR1211, a pan-RXR antagonist, whereas a pan-RXR agonist, UVI2108, mimicked DHA activities. Retinoic acid (RA), a natural ligand of RXRs, also reduced despair behavior and improved working memory and such activities did not require activation of RARs, as RA effects were abolished by co-treatment with BR1211 and they were not reproduced by TTNPB, a pan-RAR agonist. The RXRγ knockout mice displayed increased despair and deficits in working memory, which were insensitive to DHA and pan-RXR agonist treatments, whereas DHA or UVI2108 reversed these deficits in RXRγ heterozygous mice.
  
  
  CONCLUSIONS
  Our data suggest that RXRs are a converging point in mediating DHA and RA modulations of despair behavior and working memory and that RXRγ is the predominant RXR isotype in these regulations.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centres National de Recherche Scientifique/Institut National de Santé et de Recherche Médicale/Université de Strasbourg/Collège de France, Strasbourg, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Wietrzych-Schindler
authors.forename: Monika
authors.initials: M
authors.lastname: Szyszka-Niagolov
authors.forename: Kiminori
authors.initials: K
authors.lastname: Ohta
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Endo
authors.forename: Efrén
authors.initials: E
authors.lastname: Pérez
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krezel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003863:Depression / Q000235:genetics / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D047491:Retinoid X Receptor gamma / Q000235:genetics / Q000378:metabolism*
chemical_list: D047491:Retinoid X Receptor gamma; D004281:Docosahexaenoic Acids