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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.

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


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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