Deletion of CREB-regulated transcription coactivator 1 induces pathological aggression, depression-related behaviors, and neuroplasticity genes dysregulation in mice

Biol Psychiatry. 2012 Oct 1;72(7):528-36. doi: 10.1016/j.biopsych.2012.04.011. Epub 2012 May 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggression / drug effects
  • Aggression / physiology*
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Antidepressive Agents, Second-Generation / therapeutic use
  • Arabidopsis Proteins / metabolism
  • Biogenic Monoamines / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Chromatography, High Pressure Liquid
  • Corticosterone / blood
  • Depressive Disorder / drug therapy
  • Depressive Disorder / genetics*
  • Depressive Disorder / metabolism
  • Disease Models, Animal
  • Electroshock / adverse effects
  • Enzyme-Linked Immunosorbent Assay
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Fear / drug effects
  • Fear / psychology
  • Female
  • Fluoxetine / pharmacology
  • Fluoxetine / therapeutic use
  • Food Preferences / drug effects
  • Food Preferences / physiology
  • Gene Expression Regulation / genetics*
  • Hindlimb Suspension
  • Intramolecular Transferases / metabolism
  • Male
  • Maternal Behavior / drug effects
  • Maternal Behavior / physiology
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nesting Behavior / drug effects
  • Nesting Behavior / physiology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics*
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism
  • Sexual Behavior, Animal / drug effects
  • Sexual Behavior, Animal / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Social Behavior
  • Swimming / psychology
  • Transcription Factors / deficiency*
  • Transcription Factors / metabolism


  • Antidepressive Agents, Second-Generation
  • Arabidopsis Proteins
  • Biogenic Monoamines
  • Brain-Derived Neurotrophic Factor
  • Crtc1 protein, mouse
  • Orphan Nuclear Receptors
  • Transcription Factors
  • Fluoxetine
  • Receptor, trkB
  • Intramolecular Transferases
  • marneral synthase, Arabidopsis
  • Corticosterone