Sex-dependent adaptive changes in serotonin-1A autoreceptor function and anxiety in Deaf1-deficient mice

Mol Brain. 2016 Aug 3;9(1):77. doi: 10.1186/s13041-016-0254-y.


The C (-1019) G rs6295 promoter polymorphism of the serotonin-1A (5-HT1A) receptor gene is associated with major depression in several but not all studies, suggesting that compensatory mechanisms mediate resilience. The rs6295 risk allele prevents binding of the repressor Deaf1 increasing 5-HT1A receptor gene transcription, and the Deaf1-/- mouse model shows an increase in 5-HT1A autoreceptor expression. In this study, Deaf1-/- mice bred on a mixed C57BL6-BALB/c background were compared to wild-type littermates for 5-HT1A autoreceptor function and behavior in males and females. Despite a sustained increase in 5-HT1A autoreceptor binding levels, the amplitude of the 5-HT1A autoreceptor-mediated current in 5-HT neurons was unaltered in Deaf1-/- mice, suggesting compensatory changes in receptor function. Consistent with increased 5-HT1A autoreceptor function in vivo, hypothermia induced by the 5-HT1A agonist DPAT was augmented in early generation male but not female Deaf1-/- mice, but was reduced with succeeding generations. Loss of Deaf1 resulted in a mild anxiety phenotype that was sex-and test-dependent, with no change in depression-like behavior. Male Deaf1 knockout mice displayed anxiety-like behavior in the open field and light-dark tests, while female Deaf1-/- mice showed increased anxiety only in the elevated plus maze. These data show that altered 5-HT1A autoreceptor regulation in male Deaf1-/- mice can be compensated for by generational adaptation of receptor response that may help to normalize behavior. The sex dependence of Deaf1 function in mice is consistent with a greater role for 5-HT1A autoreceptors in sensitivity to depression in men.

Keywords: Anxiety; Major depression; Raphe; Receptor signaling; Serotonin; Transgenerational.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Adaptation, Physiological*
  • Animals
  • Anxiety / complications
  • Anxiety / metabolism
  • Anxiety / physiopathology*
  • Behavior, Animal / drug effects
  • DNA-Binding Proteins
  • Depression / complications
  • Depression / metabolism
  • Depression / physiopathology
  • Female
  • Hypothermia, Induced
  • Ion Channel Gating / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin / pharmacology
  • Sex Characteristics*
  • Transcription Factors / deficiency*
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • Deaf1 protein, mouse
  • Transcription Factors
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • 8-Hydroxy-2-(di-n-propylamino)tetralin