Citation

Vahid-Ansari F, Daigle M, Manzini MC, Tanaka KF, Hen R, Geddes SD, Béïque JC, James J, Merali Z, Albert PR. J. Neurosci. 2017; 37(49): 11967-11978.

Affiliation

Ottawa Hospital Research Institute (Neuroscience), UOttawa Brain and Mind Research Institute, Ottawa ON K1H-8M5 Canada palbert@uottawa.ca.

Copyright

(Copyright © 2017, Society for Neuroscience)

DOI

10.1523/JNEUROSCI.1668-17.2017

PMID

29101244

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 knockout 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 knockout (cF1/1A dko) to disrupt both Freud-1 and 5-HT1A genes in 5-HT neurons, no increase in anxiety- or depression-like behaviour was seen upon knockout of Freud-1 on the 5-HT1A autoreceptor-negative background, rather a reduction in depression-like behaviour emerged. These studies implicate transcriptional dys-regulation 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 like Freud-1 to restore transcriptional balance may augment response to antidepressant treatment.SIGNIFICANCE STATEMENTAltered 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 up-regulation of 5-HT1A autoreceptors to anxiety/depression-like behavior and provides a new model of antidepressant resistance. Treatment strategies to re-establish transcriptional regulation of 5-HT1A autoreceptors could provide more robust and sustained antidepressant response.

Copyright © 2017 the authors.

Language: en