Abrogated freud-1/Cc2d1a repression of 5-HT1A autoreceptors induces fluoxetine-resistant anxiety/ depression-like behavior

Faranak Vahid-Ansari, Mireille Daigle, M. Chiara Manzini, Kenji F. Tanaka, René Hen, Sean D. Geddes, Jean Claude Béïque, Jonathan James, Zul Merali, Paul R. Albert

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Freud-1/Cc2d1a represses the gene transcription of serotonin-1A (5-HT1A) autoreceptors, which negatively regulate 5-HT tone. To test the role of Freud-1 in vivo, we generated mice with adulthood conditional knock-out of Freud-1 in 5-HT neurons (cF1ko). In cF1ko mice, 5-HT1A autoreceptor protein, binding and hypothermia response were increased, with reduced 5-HT content and neuronal activity in the dorsal raphe. The cF1ko mice displayed increased anxiety- and depression-like behavior that was resistant to chronic antidepressant (fluoxetine) treatment. Using conditional Freud-1/5-HT1A double knock-out (cF1/1A dko) to disrupt both Freud-1 and 5-HT1A genes in 5-HT neurons, no increase in anxiety- or depression-like behavior was seen upon knock-out of Freud-1 on the 5-HT1A autoreceptor-negative background; rather, a reduction in depression-like behavior emerged. These studies implicate transcriptional dysregulation of 5-HT1A autoreceptors by the repressor Freud-1 in anxiety and depression and provide a clinically relevant genetic model of antidepressant resistance. Targeting specific transcription factors, such as Freud-1, to restore transcriptional balance may augment response to antidepressant treatment.

Original languageEnglish
Pages (from-to)11967-11978
Number of pages12
JournalJournal of Neuroscience
Volume37
Issue number49
DOIs
Publication statusPublished - 2017 Dec 6

Keywords

  • 5-HT1A receptor
  • Anxiety
  • Major depression
  • Raphe
  • Repressor
  • Serotonin

ASJC Scopus subject areas

  • Neuroscience(all)

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