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Research Articles, Cellular/Molecular

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 and Paul R. Albert
Journal of Neuroscience 6 December 2017, 37 (49) 11967-11978; DOI: https://doi.org/10.1523/JNEUROSCI.1668-17.2017
Faranak Vahid-Ansari
1Ottawa Hospital Research Institute (Neuroscience), University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H-8M5, Canada,
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Mireille Daigle
1Ottawa Hospital Research Institute (Neuroscience), University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H-8M5, Canada,
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M. Chiara Manzini
2Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037,
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Kenji F. Tanaka
3Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan,
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René Hen
4Department of Psychiatry, Columbia University Medical Center and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, New York 10032,
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Sean D. Geddes
5Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa K1H-8M5 Canada, and
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Jean-Claude Béïque
5Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa K1H-8M5 Canada, and
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Jonathan James
6The Royal's Institute of Mental Health, affiliated with the University of Ottawa, Ottawa, Ontario, K1Z-7K4 Canada
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Zul Merali
5Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa K1H-8M5 Canada, and 6The Royal's Institute of Mental Health, affiliated with the University of Ottawa, Ottawa, Ontario, K1Z-7K4 Canada
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Paul R. Albert
1Ottawa Hospital Research Institute (Neuroscience), University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H-8M5, Canada,
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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.

SIGNIFICANCE STATEMENT Altered regulation of the 5-HT1A autoreceptor has been implicated in human anxiety, major depression, suicide, and resistance to antidepressants. This study uniquely identifies a single transcription factor, Freud-1, as crucial for 5-HT1A autoreceptor expression in vivo. Disruption of Freud-1 in serotonin neurons in mice links upregulation of 5-HT1A autoreceptors to anxiety/depression-like behavior and provides a new model of antidepressant resistance. Treatment strategies to reestablish transcriptional regulation of 5-HT1A autoreceptors could provide a more robust and sustained antidepressant response.

  • 5-HT1A receptor
  • anxiety
  • major depression
  • raphe
  • repressor
  • serotonin
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The Journal of Neuroscience: 37 (49)
Journal of Neuroscience
Vol. 37, Issue 49
6 Dec 2017
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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
Journal of Neuroscience 6 December 2017, 37 (49) 11967-11978; DOI: 10.1523/JNEUROSCI.1668-17.2017

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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
Journal of Neuroscience 6 December 2017, 37 (49) 11967-11978; DOI: 10.1523/JNEUROSCI.1668-17.2017
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Keywords

  • 5-HT1A receptor
  • anxiety
  • major depression
  • raphe
  • repressor
  • serotonin

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