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J Neurosci. 2017 Dec 6;37(49):11967-11978. doi: 10.1523/JNEUROSCI.1668-17.2017. Epub 2017 Nov 3.

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior.

Author information

1
Ottawa Hospital Research Institute (Neuroscience), University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H-8M5, Canada.
2
Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037.
3
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, 160-8582, Japan.
4
Department of Psychiatry, Columbia University Medical Center and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, New York 10032.
5
Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa K1H-8M5 Canada, and.
6
The Royal's Institute of Mental Health, affiliated with the University of Ottawa, Ottawa, Ontario, K1Z-7K4 Canada.
7
Ottawa Hospital Research Institute (Neuroscience), University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H-8M5, Canada, palbert@uottawa.ca.

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.

KEYWORDS:

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

PMID:
29101244
PMCID:
PMC5722640
DOI:
10.1523/JNEUROSCI.1668-17.2017
[Indexed for MEDLINE]
Free PMC Article

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