Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

Figure 1 Brain-derived neurotrophic factor signaling cascade diagram. When TrkB is activated by binding mature brain-derived neurotrophic factor (BDNF), the intracellular domains of the receptor dimerize and autophosphorylate one of three tyrosine residues. Phosphorylation at each residue initiates a distinct signaling cascade: Ras-PI3K-Akt, Ras-MAP kinase-Erk, or phospholipase Cγ. These signaling cascades activate transcription factor CREB, resulting in cell proliferation, cell survival, synaptogenesis, and memory formation. ProBDNF binds to pan-neurotrophin receptor P75^NTR. P75^NTR signaling activates transcription factor NFκB, leading to inflammation and apoptosis. BDNF: Brain-derived neurotrophic factor.

Figure 2 Hypothesis diagram. Brain-derived neurotrophic factor (BDNF) deficiency and elevated or chronic neuroinflammation independently confer vulnerability to development of major depressive disorder. BDNF plays a negative regulatory role in resolving neuroinflammation, and high inflammation reduces BDNF expression. BDNF: Brain-derived neurotrophic factor. BDNF: Brain-derived neurotrophic factor.

Figure 3 Inflammation shifts kynurenine metabolism pathway towards oxidative stress-associated metabolites. The enzyme indolamine-2,3-dioxygenase (IDO) converts tryptophan to kynurenine. Kynurenine aminotransferase converts kynurenine to kynureninic acid in astrocytes while kynurenine monooxygenase (KMO) metabolizes kynurenine to 3-hyroxykynurenine (3-HK) in microglia. 3-HK is metabolized by kynureninase to 3-hydroxyanthranilic acid and 3-hydroxyanthranilic acid dioxygenase to quinolinic acid. Inflammation up-regulates the enzymes IDO and KMO, resulting in increased levels of KMO-dependent metabolites associated with oxidative stress and depression. IDO: Indolamine-2,3-dioxygenase; KAT: Kynurenine aminotransferase; KMO: Kynurenine monooxygenase; 3-HK: 3-hyroxykynurenine; KYNU: Kynureninase; HAAO: 3-hydroxyanthranilic acid dioxygenase; QA: Quinolinic acid.

Figure 4 Brain-derived neurotrophic factor deficiency impairs resolution of microglial inflammatory phenotypes. Brain-derived neurotrophic factor (BDNF) levels are altered by genetics and environmental circumstances. Reduced levels of BDNF impair microglia regulation after inflammation. Hyper-active microglia contribute to blood-brain barrier disruption and express higher levels of pro-inflammatory cytokines and kynurenine metabolism pathway enzymes. Individuals with hyper-active microglia are vulnerable to developing symptoms of depression after inflammatory challenge. BDNF: Brain-derived neurotrophic factor.