Background
Mood disorders are polygenic disorders in which the alteration of several susceptibility
genes results in dysfunctional mood regulation. However, the molecular mechanisms
underlying their transcriptional dysregulation are still unclear. The transcription
factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)
and the neurotrophin brain-derived neurotrophic factor (BDNF) have been implicated
in rodent models of depression. We previously provided evidence that Bdnf expression critically rely on a potent CREB coactivator called CREB-regulated transcription
coactivator 1 (CRTC1).
Methods
To further evaluate the role of CRTC1 in the brain, we generated a knockout mouse
line and analyzed its behavioral and molecular phenotype.
Results
We found that mice lacking CRTC1 associate neurobehavioral endophenotypes related
to mood disorders. Crtc1–/– mice exhibit impulsive aggressiveness, social withdrawal, and decreased sexual motivation,
together with increased behavioral despair, anhedonia, and anxiety-related behavior
in the novelty-induced hypophagia test. They also present psychomotor retardation
as well as increased emotional response to stressful events. Crtc1–/– mice have a blunted response to the antidepressant fluoxetine in behavioral despair
paradigms, whereas fluoxetine normalizes their aggressiveness and their behavioral
response in the novelty-induced hypophagia test. Crtc1−/− mice strikingly show, in addition to a reduced dopamine and serotonin turnover in
the prefrontal cortex, a concomitant decreased expression of several susceptibility
genes involved in neuroplasticity, including Bdnf, its receptor TrkB, the nuclear receptors Nr4a1-3, and several other CREB-regulated genes.
Conclusions
Collectively, these findings support a role for the CRTC1-CREB pathway in mood disorders
etiology and behavioral response to antidepressants and identify CRTC1 as an essential
coactivator of genes involved in mood regulation.
Key Words
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Article info
Publication history
Published online: May 17, 2012
Accepted:
April 7,
2012
Received in revised form:
March 15,
2012
Received:
July 14,
2011
Footnotes
Authors CR, EMM, and CM contributed equally to this work.
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
