Increased EphA4-ephexin1 signaling in the medial prefrontal cortex plays a role in depression-like phenotype

Sci Rep. 2017 Aug 2;7(1):7133. doi: 10.1038/s41598-017-07325-2.


Accumulating evidence suggests a role of the ephrin receptor EphA4 and the downstream protein ephexin1 in synaptic plasticity, which is implicated in depression. We examined whether EphA4-ephexin1 signaling plays a role in the pathophysiology of depression, and the antidepressant-like effect of EphA4 inhibitor rhynchophylline. We found increased ratios of p-EphA4/EphA4 and p-ephexin1/ephexin1 in the prefrontal cortex (PFC) and hippocampus but not in the nucleus accumbens (NAc), of susceptible mice after social defeat stress. Furthermore, the p-EphA4/EphA4 ratio was higher in the parietal cortex of depressed patients compared with controls. Systemic administration of rhynchophylline, produced a rapid antidepressant-like effect in a social defeat stress model by inhibiting EphA4-ephexin1 signaling and activating brain-derived neurotrophic factor-TrkB signaling in the PFC and hippocampus. Pretreatment with rhynchophylline before each social defeat stress could prevent the onset of the depression-like phenotype after repeated social defeat stress. Overexpression of EphA4 in the medial PFC owing to infection with an EphA4 adeno-associated virus caused the depression-like phenotype 3 weeks later and rhynchophylline had a rapid antidepressant-like effect in these mice. These findings suggest that increased EphA4-ephexin1 signaling in the PFC plays a role in the pathophysiology of depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Behavior, Animal
  • Biomarkers
  • Brain / metabolism
  • Brain / physiopathology
  • Depression / drug therapy
  • Depression / metabolism*
  • Depression / psychology*
  • Disease Models, Animal
  • Disease Susceptibility
  • Female
  • Gene Expression
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Male
  • Mice
  • Models, Biological
  • Oxindoles / pharmacology
  • Phenotype*
  • Phosphorylation
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / physiopathology
  • Rats
  • Receptor, EphA4 / genetics
  • Receptor, EphA4 / metabolism*
  • Signal Transduction*
  • Social Behavior
  • Stress, Psychological


  • Antidepressive Agents
  • Biomarkers
  • Guanine Nucleotide Exchange Factors
  • Oxindoles
  • rhyncophylline
  • Receptor, EphA4