The Role of Brain-derived Neurotrophic Factor in Depression
Jemynna Haley Chua
Introduction. Depression is a mood disorder characterized by sadness or irritability, accompanied by several psychophysiological changes.1 Depression affects more than 300 million globally and is the leading cause of disability worldwide.2 Brain-derived neurotrophic factor (BDNF), a neurotrophin, facilitates neuronal survival, migration, differentiation, growth, and synaptic plasticity.3 BDNF is essential for the outgrowth and activity- dependent remodeling of axonal arbors in vivo and plays a role in the embryonal neurodevelopment of dopaminergic, noradrenergic, and serotonergic neurons.4 The precursor protein, proBDNF, is converted to the active proteins BDNF pro-peptide and mature BDNF, which elicit opposing effects via the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase B receptor (TrkB), respectively.5 While mature BDNF regulates neuronal survival, BDNF pro-peptide and proBDNF regulate neuronal cell death.3 With a better understanding of BDNF, novel approaches may be developed for the treatment of refractory depression. Methods. To determine the role of BDNF in depression, protein expression of BDNF pro-peptide and mature BDNF was measured in the parietal cortex of postmortem human samples.5 Another study examined the expression of proBDNF in the brain of stress-induced mice.3 Results. Expression of BDNF pro-peptide in the parietal cortex of the Major Depressive Disorder (MDD) group was significantly higher than controls, while mature BDNF in the parietal cortex was significantly lower in MDD group compared to controls.5 Inducing depression-like behaviors in mice significantly increased proBDNF levels in the neocortex and hippocampus of the mice.3 Additionally, proBDNF-p75NTR apoptotic signaling was activated in brains of stress-induced mice, while transcriptional and translational levels of TrkB in the neocortex and hippocampus of these mice were decreased compared to controls.3 RT-PCR showed significantly increased levels of Ngfr (gene for p75NTR), but decreased mRNA levels of Bdnf and TrkB in the neocortex and hippocampus of stress-induced mice compared to controls.3 Discussion. Studies suggest that increased BDNF pro-peptide-p75NTR signaling and decreased BDNF-TrKB signaling in the parietal cortex is crucial to the pathophysiology of MDD.5 Chronic stress may activate the proBDNF- p75NTR neurodegenerative signaling pathway and inhibit the BDNF-TrkB cell survival signaling pathway, so imbalance between the two opposing pathways may contribute to the pathogenesis of MDD and neurodegeneration during stress.3 Targeting central or peripheral proBDNF via Intracerebroventricular and intraperitoneal injections of anti-proBDNF antibodies may be considered as a treatment option for pharmacoresistant depression.3 Restoration of the balance between proBDNF and mature BDNF by inhibiting BDNF or supplementing mature BDNF may be implemented as a novel approach to depression.3
- Belmaker RH, Agam G. Major depressive disorder. N Engl J Med. 2008;358(1):55-68. doi:10.1056/NEJMra073096 [doi].
- Depression. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/depression.Published March 22, 2018. Accessed May 3, 2019.
- Bai YY, Ruan CS, Yang CR, et al. ProBDNF signaling regulates depression-like behaviors in rodents under chronic stress. Neuropsychopharmacology. 2016;41(12):2882-2892. doi: 10.1038/npp.2016.100 [doi].
- Deuschle M, Hendlmeier F, Witt S, et al. Cortisol, cortisone, and BDNF in amniotic fluid in the second trimester of pregnancy: Effect of early life and current maternal stress and socioeconomic status. Dev Psychopathol. 2018;30(3):971-980. doi: 10.1017/S0954579418000147 [doi].
- Yang B, Ren Q, Zhang JC, Chen QX, Hashimoto K. Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: Rethinking the brain- liver axis. Transl Psychiatry. 2017;7(5):e1128. doi: 10.1038/tp.2017.95 [doi].