Down-regulation of the Trk-B signal pathway: the possible pathogenesis of major depression

Med Hypotheses. 2004;62(2):215-8. doi: 10.1016/S0306-9877(03)00299-8.


Major depressive disorder (MDD) is a common mental disease with unknown etiology. Recent studies have suggested that decreased brain-derived neurotrophic factor (BDNF) may be implicated in the pathogenesis of MDD. Instead of a decrease in central BDNF, however, studies utilizing genetic depression animal models have found elevated levels of the factor. In the brain, BDNF exerts its influence chiefly by signaling through tyrosine receptor kinase B (Trk-B). In this report, it is suggested that Trk-B pathway down-regulation may be the major pathogenesis for MDD, while stress, which may reduce central BDNF, acts as a precipitation factor to further dampen central BDNF activity and contribute to the development of depression. Further, several possible mechanisms of Trk-B pathway down-regulation, and the implications for this down-regulation in MDD are discussed.

MeSH terms

  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Depressive Disorder, Major / metabolism*
  • Down-Regulation
  • Humans
  • Models, Biological
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, trkB / metabolism*
  • Signal Transduction*
  • Stress, Physiological / complications
  • Stress, Physiological / metabolism*


  • Brain-Derived Neurotrophic Factor
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkB