Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

Neuron. 2015 Aug 5;87(3):549-62. doi: 10.1016/j.neuron.2015.07.010.


Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrier Proteins / biosynthesis*
  • Depression / metabolism*
  • Depression / psychology
  • Depression / therapy
  • Homer Scaffolding Proteins
  • Humans
  • Imipramine / pharmacology
  • Imipramine / therapeutic use*
  • Ketamine / pharmacology
  • Ketamine / therapeutic use*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Rats
  • Receptor, Adenosine A1 / biosynthesis*
  • Receptor, Adenosine A1 / deficiency
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sleep Deprivation / metabolism*
  • Sleep Deprivation / psychology


  • Carrier Proteins
  • Homer Scaffolding Proteins
  • Receptor, Adenosine A1
  • Ketamine
  • Imipramine