The Biological Actions and Mechanisms of Brain-Derived Neurotrophic Factor in Healthy and Disordered Brains

Abstract

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that elicits neuronal survival and differentiation, synaptic transmission, and the modulation of synaptic plasticity. The biological actions of BDNF are mediated via two distinct receptors: the high-affinity tropomyosin-related kinase B (TrkB) receptor and the low-affinity p75 neurotrophin receptor (p75NTR). Recent findings regarding the actions and mechanisms of BDNF are reviewed here. Activity-dependent synaptic plasticity, as exemplified by long-term potentiation (LTP) and long-term depression (LTD), underlies the cellular mechanism of learning and memory. An accumulating body of evidence shows that BDNF modulates synaptic plasticity. This function requires extracellular neurotrophin release, synaptic activity-dependent local protein synthesis. In addition, a precursor of BDNF, proBDNF, is emerging as a new ligand with biological activities that are distinct from those of BDNF. The proteolytic cleavage of proBDNF is also proposed as a mechanism that determines the direction of BDNF actions. This review discusses the post-translational processing of proBDNF, the modulatory roles of the human BDNF polymorphism Val66Met, recent reports of the novel mechanisms of BDNF expression, and clinical reports showing the roles of BDNF in the blood. Taken together, these data provide new insights into the biological roles of BDNF and its related molecules in the central nervous system.

Potential Role of Brain-Derived Neurotrophic Factor and Dopamine Receptor D2 Gene Variants as Modifiers for the Susceptibility and Clinical Course of Wilson’s Disease

“…This may underlie the pathogenesis of neurodegeneration in WD. Previously, it has been reported that the Val66Met polymorphism impairs intracellular trafficking losing its interaction with the sortilin receptor complex (Mizui et al, 2014). In vitro cell based studies revealed that substitution of the methionine residue at this position leads to decreased distribution to the dendrites and impaired secretion (Egan et al, 2003).…”

“…in WD have been reported to occur due to basal ganglia dysfunctions and/ or neurodegeneration in other related brain structures (Das and Ray, 2006). Previous investigators have highlighted the involvement of BDNF in neurodegenerative and neuropsychiatric diseases (Mizui et al, 2014), implicating its potential involvement in WD. In the present study, we found that the C allele and CC genotype of BDNF C270T polymorphism play a protective function being significantly overrepresented among control individuals compared to WD patients.…”

“…Brain derived neurotrophic factor (BDNF), is essential for differentiation and survival of the neurons, modulating synaptic plasticity and synaptic transmission (Mizui et al, 2014). It regulates long term potentiation and long term depression functions in the hippocampal and cortical neurons, thus affecting learning and memory (Mizui et al, 2015).…”

“…Following cleavage of the signal peptide, pro-BDNF is converted to mature BDNF and BDNF pro-peptide. BDNF as dimer binds to two receptors of distinct classes: the type B tyrosine kinase receptor of the tropomyosin-related kinase family (TrkB) and the p75 receptor, which is a member of the tumor necrosis factor (TNF) receptor family (Mizui et al, 2014). Previous reports suggest that BDNF polymorphisms and reduced BDNF expression in human brains are closely related to the pathogenesis of several neurodegenerative and neuropsychiatric disorders (Autry and Monteggia, 2012).…”

Long Non-coding RNA in Neurons: New Players in Early Response to BDNF Stimulation

“…BDNF interaction with NTRK2 receptor activates three signaling pathways: PI3K-Akt (PI3K, phosphatidylinositol-3 kinase), Ras-MAPK (MAPK, mitogen-activated protein kinase), and PLCγ-Ca + (PLC, phospholipase C; Duman and Voleti, 2012 ). It is also known to regulate a large spectrum of processes of the nervous system, including cell survival, growth, and differentiation ( Casaccia-Bonnefil et al, 1999 ; Bibel and Barde, 2000 ; Huang and Reichardt, 2003 ; Park and Poo, 2013 ; Suliman et al, 2013 ; Zagrebelsky and Korte, 2014 ), synaptic plasticity of neurons, and LTP ( Xu et al, 2000 ; Bramham and Messaoudi, 2005 ; Gottmann et al, 2009 ; Minichiello, 2009 ; Mizui et al, 2014 ; Zagrebelsky and Korte, 2014 ; Leal et al, 2015 ). BDNF’s roles in neuronal processes during development and adulthood, support its potential role in the pathogenesis and treatment of both neurological and psychiatric disorders ( Pruunsild et al, 2007 ; Nagahara and Tuszynski, 2011 ; Weissmiller and Wu, 2012 ).…”