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TitleAbrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior.
Publication TypeJournal Article
Year of Publication2017
AuthorsVahid-Ansari, Faranak, Mireille Daigle, Chiara M Manzini, Kenji F. Tanaka, René Hen, Sean D. Geddes, Jean-Claude Béïque, Jonathan James, Zul Merali, and Paul R. Albert
JournalJ Neurosci
Volume37
Issue49
Pagination11967-11978
Date Published2017 Dec 06
ISSN1529-2401
KeywordsAnimals, Antidepressive Agents, Second-Generation, Anxiety, Autoreceptors, Brain, Depressive Disorder, Treatment-Resistant, Female, Fluoxetine, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptor, Serotonin, 5-HT1A, Repressor Proteins, Serotonergic Neurons
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 , we generated mice with adulthood conditional knock-out of Freud-1 in 5-HT neurons (). In mice, 5-HT1A autoreceptor protein, binding and hypothermia response were increased, with reduced 5-HT content and neuronal activity in the dorsal raphe. The 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 () 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. 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 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.

DOI10.1523/JNEUROSCI.1668-17.2017
Alternate JournalJ. Neurosci.
PubMed ID29101244
PubMed Central IDPMC5722640
Grant List115098-1 / / Canadian Institutes of Health Research / Canada
123426-1 / / Canadian Institutes of Health Research / Canada