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

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Faranak Vahid-AnsariPaul R Albert

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 Alte...Continue Reading

Citations

Dec 25, 2019·Journal of Neuroscience Research·Adele Mossa, M Chiara Manzini
Apr 22, 2018·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Haiyan LiTakashi Shiga
Sep 7, 2020·Scandinavian Journal of Pain·Sepideh Saffarpour, Farinaz Nasirinezhad
Jan 9, 2019·Frontiers in Neuroscience·Emily QuentinLuc Maroteaux
Aug 28, 2021·International Journal of Molecular Sciences·Grzegorz ŚlifirskiJadwiga Turło

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