TY  - JOUR
PY  - 2017//
TI  - Abrogated Freud-1/CC2D1A repression of 5-HT1A autoreceptors induces fluoxetine-resistant anxiety/depression-like behavior
JO  - Journal of neuroscience
A1  - Vahid-Ansari, Faranak
A1  - Daigle, Mireille
A1  - Manzini, M. Chiara
A1  - Tanaka, Kenji F.
A1  - Hen, René
A1  - Geddes, Sean D.
A1  - Béïque, Jean-Claude
A1  - James, Jonathan
A1  - Merali, Zul
A1  - Albert, Paul R.
SP  - 11967
EP  - 11978
VL  - 37
IS  - 49
N2  - 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.<br><br>Copyright © 2017 the authors.<p />  <p>Language: en</p>
LA  - en
SN  - 0270-6474
UR  - http://dx.doi.org/10.1523/JNEUROSCI.1668-17.2017
ID  - ref1
ER  -