Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0020672 (
hypothermia
)
17,327
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior. 2910 Dec 44
