Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment

• Published in: Neuroscience and biobehavioral reviews 2018-07, Vol.90, p.70-83
• Main Authors: Diniz, Cassiano R.A.F., Casarotto, Plinio C, Resstel, Leonardo, Joca, Sâmia R.L.
• Format: Article
• Language: English
• Subjects: Antidepressive Agents - therapeutic use; BDNF; Brain - drug effects; Brain - metabolism; Brain-Derived Neurotrophic Factor - metabolism; Continuum-sorting hypothesis; Depression; Depression - drug therapy; Depression - metabolism; Neuronal Plasticity - drug effects; Neurons - drug effects; Neurons - metabolism; proBDNF/BDNF-propeptide; PTSD; Stress
• ISSN: 0149-7634; 1873-7528
• DOI: 10.1016/j.neubiorev.2018.04.001

•Stress and antidepressants modulate brain neuroplasticity and BDNF levels.•BDNF production is tied to previous proBDNF making.•Binary sorting hypothesis proposes BDNF/proBDNF balance as crucial to neuroremodeling.•Neuronal remodeling is necessary for antidepressant effects on anxiety and depression. Depression and posttraumatic stress disorder are assumed to be maladaptive responses to stress and antidepressants are thought to counteract such responses by increasing BDNF (brain-derived neurotrophic factor) levels. BDNF acts through TrkB (tropomyosin-related receptor kinase B) and plays a central role in neuroplasticity. In contrast, both precursor proBDNF and BDNF propeptide (another metabolic product from proBDNF cleavage) have a high affinity to p75 receptor (p75R) and usually convey apoptosis and neuronal shrinkage. Although BDNF and proBDNF/propeptide apparently act in opposite ways, neuronal turnover and remodeling might be a final common way that both act to promote more effective neuronal networking, avoiding neuronal redundancy and the misleading effects of environmental contingencies. This review aims to provide a brief overview about the BDNF functional role in antidepressant action and about p75R and TrkB signaling to introduce the “continuum-sorting hypothesis.” The resulting hypothesis suggests that both BDNF/proBDNF and BDNF/propeptide act as protagonists to fine-tune antidepressant-dependent neuroplasticity in crucial brain structures to modulate behavioral responses to stress.