Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are broadly expressed in the developing and adult mammalian brain. BDNF / TrkB-stimulated intracellular signaling is critical for neuronal survival, morphogenesis, and plasticity. It is well known that binding of BDNF to TrkB elicits various intracellular signaling pathways, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK / ERK), phospholipaseCγ (PLCγ), and phosphoinositide 3-kinase (PI3K) pathways, and that BDNF exerts biological effects on neurons via activation of similar mechanisms. The producer of these BDNF signaling / pathway can be described as follows. (1) BDNF binds to tyrosine kinase receptor type-B and induces the dimerization of the receptor. (2) Binding of BDNF induces TrkB autophosphorylation at specific tyrosine residues of the receptor and thus creates binding sites for specific proteins. (3) Three main intracellular signalling cascades are activated by TrkB: Rasmitogen- activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and the PLCg-Ca2+ pathway. (4) Activation of PLC-g leads to the release of calcium from the endoplasmic reticulum and to activation of a calcium-calmodulindependent kinase II (CAMKII), ending in phosphorylation of CREB and activation of transcription. Activation of the MAPK pathway can also regulate transcription through phosphorylation of CREB. (5) Signaling pathways mediate BDNF-promoted modifications of dendritic morphology. Simultaneous triggering of the PI3K and MAPK pathways concurrently alters both actin and microtubule dynamics and changes downstream dendrite branching.
In addition to TrkB, a low-affinity receptor p75 is also involved in neuronal survival and plasticity. BDNF affects neurons positively or negatively through various intracellular signaling pathways triggered by activation of TrkB or p75. From a clinical standpoint, roles of BDNF have been implicated in the pathophysiology of various brain diseases. The stress-induced steroid hormone, glucocorticoid, and BDNF are putatively associated with the pathophysiology of depression.