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.
Highlights
Levi-Montalcini and Hamburger first discovered that a mouse sarcoma tumor implanted near the spinal cord of the developing chicken released a soluble protein that increased neurite outgrowth from sympathetic neurons [1]
brain-derived neurotrophic factor (BDNF) and its pro-peptide are present in hippocampal extracts at similar concentrations [25], suggesting that both peptides are stored after cleavage
BDNF-mediated regulation of spine formation in the dendrites of hippocampal neurons is controlled by cyclic AMP, a signaling molecule involved in late-long-term potentiation (LTP) [40]
Summary
Levi-Montalcini and Hamburger first discovered that a mouse sarcoma tumor implanted near the spinal cord of the developing chicken released a soluble protein that increased neurite outgrowth from sympathetic neurons [1]. This factor is named nerve growth factor (NGF) [2]-[4]. BDNF is highly homologous to NGF at the amino acid sequence level. This finding led to the identification of two additional neurotrophins: neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) [7]-[9]. Since this report, accumulating evidence suggests that the Val66Met genetic variant increases the susceptibility of an individual to a variety of brain disorders [13]
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