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 Tanaka, René Hen, Sean D. Geddes, Jean Claude Béïque, Jonathan James, Zul Merali, Paul R. Albert

研究成果: Article

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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.

元の言語English
ページ(範囲)11967-11978
ページ数12
ジャーナルJournal of Neuroscience
37
発行部数49
DOI
出版物ステータスPublished - 2017 12 6

ASJC Scopus subject areas

  • Neuroscience(all)

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    Vahid-Ansari, F., Daigle, M., Manzini, M. C., Tanaka, K., Hen, R., Geddes, S. D., Béïque, J. C., James, J., Merali, Z., & Albert, P. R. (2017). Abrogated freud-1/Cc2d1a repression of 5-HT1A autoreceptors induces fluoxetine-resistant anxiety/ depression-like behavior. Journal of Neuroscience, 37(49), 11967-11978. https://doi.org/10.1523/JNEUROSCI.1668-17.2017