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Review
, 38 (3), 579-593

BDNF: A Key Factor With Multipotent Impact on Brain Signaling and Synaptic Plasticity

Affiliations
Review

BDNF: A Key Factor With Multipotent Impact on Brain Signaling and Synaptic Plasticity

Przemysław Kowiański et al. Cell Mol Neurobiol.

Abstract

Brain-derived neurotrophic factor (BDNF) is one of the most widely distributed and extensively studied neurotrophins in the mammalian brain. Among its prominent functions, one can mention control of neuronal and glial development, neuroprotection, and modulation of both short- and long-lasting synaptic interactions, which are critical for cognition and memory. A wide spectrum of processes are controlled by BDNF, and the sometimes contradictory effects of its action can be explained based on its specific pattern of synthesis, comprising several intermediate biologically active isoforms that bind to different types of receptor, triggering several signaling pathways. The functions of BDNF must be discussed in close relation to the stage of brain development, the different cellular components of nervous tissue, as well as the molecular mechanisms of signal transduction activated under physiological and pathological conditions. In this review, we briefly summarize the current state of knowledge regarding the impact of BDNF on regulation of neurophysiological processes. The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted.

Keywords: BDNF; Cognition; Development; Neurotrophin; Synaptic plasticity.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic presentation of synthesis and maturation of BDNF. BDNF synthesis and maturation is a multistage sequence of intra- and extracellular processes. In the intracellular pathway, the pre-pro-BDNF precursor sequence is produced in the endoplasmic reticulum and transported to the Golgi apparatus. In the course of intracellular cleavage, the pre-region sequence is removed, resulting in formation of immature proneurotrophin isoform of BDNF (pro-BDNF). Further, after removal of the pro-domain sequence, the mature isoform of BDNF (m-BDNF) is produced. Intracellular cleavage leading to formation of m-BDNF also occurs in intracellular vesicles, allowing transport of this neurotrophin to axonal terminals and subsequent release into the extracellular space, via presynaptic membrane. Processing of BDNF is accomplished by intracellular proteases, regulated convertases, and furin. As a result, both pro-BDNF and m-BDNF isoforms are released into the extracellular space. In the extracellular pathway, pro-BDNF released into the extracellular space is processed by metalloproteinases 2 and 9 (MMP2 and MMP9), plasmin, and extracellular proteases. Consequently, functionally effective isoforms of m-BDNF and pro-BDNF can be found in the extracellular space. BDNF brain-derived neurotrophic factor, m-BDNF mature isoform of BDNF, MMP2 metalloprotease 2, MMP9 metalloprotease 9, pre-pro-BDNF primary, uncleaved precursor form of BDNF, pre-region region of precursor sequence, pro-BDNF proneurotrophin isoform of BDNF after cleavage of pre-region precursor sequence, pro-domain sequence cleaved from proneurotrophin isoform of BDNF when it becomes mature BDNF
Fig. 2
Fig. 2
Interaction of BDNF isoforms with specific receptors. As a consequence of intra- or extracellular cleavage, the primary sequence of pre-pro-BDNF is divided into functionally active isoforms of pro-domain, pro-BDNF, and m-BDNF, each of which exhibits characteristic affinity to a specific type of receptor. The BDNF pro-domain binds preferentially to the sortilin receptor. Although the Val66Met polymorphism of the pro-domain does not exclude its binding with sortilin, the receptor affinity and functional effects resulting from Val66 or Met66 pro-domain binding are characteristic for each of them. The pro-BDNF isoform consisting of two sequences (pro-domain and mature domain) interacts with specific receptors (sortilin and p75NTR, respectively). The mature domain of BDNF, being the only constituent of the m-BDNF isoform, exhibits highest affinity for the TrkB receptor, which when stimulated undergoes homodimerization and autophosphorylation. P phosphate group, p75NTR p75 neurotrophin receptor, sortilin sortilin-related vacuolar protein sorting 10 protein (Vps10p)-domain sorting receptor 2, TrkB tyrosine kinase B receptor, Val66Met polymorphism polymorphism of BDNF pro-domain resulting from methionine to valine substitution at position 66 within the BDNF gene in the pro-domain encoding region
Fig. 3
Fig. 3
Intracellular signaling cascades activated by interaction of pro-BDNF isoform with p75NTR and sortilin receptors. The sequences of pro-domain and mature domain (m-BDNF), which form the proneurotrophin isoform (pro-BDNF), reveal preferential affinity for sortilin and p75NTR, respectively. This results in formation of pro-BDNF/p75NTR/sortilin binding complex and triggering of signaling pathways related with RhoA, NF-κB and JNK, which promotes processes leading to neuronal development and survival, but also to programmed cell death. JNK c-Jun amino terminal kinase, NF-κB nuclear factor kappa B, p75NTR p75 neurotrophin receptor, pro-BDNF proneurotrophin isoform of BDNF, RhoA Ras homolog gene family member A, sortilin sortilin-related Vps10p-domain sorting receptor 2
Fig. 4
Fig. 4
Intracellular signaling cascades activated by interaction of m-BDNF isoform with TrkB receptor. Binding of the m-BDNF isoform to TrkB receptor triggers its homodimerization and phosphorylation with subsequent translocation to cellular membrane lipid rafts, rich in cholesterol and sphingolipids. The m-BDNF/TrkB receptor complex triggers signaling pathways associated with activation of PI3K, MAPK, PLC- γ, and GTP-ases of the Rho family. CAM kinase Ca2+-calmodulin-dependent protein kinase, CREB cAMP response element-binding protein, DAG 1,2-diacylglycerol, ERK extracellular-signal-regulated kinase, GTP-ases guanosine triphosphate hydrolases, MAPK mitogen-activated protein kinase, m-BDNF mature isoform of BDNF, NMDAR N-methyl-d-aspartate receptor, P phosphate group, PI3K phosphatidylinositol 3-kinase, PKC protein kinase C, PLC-γ phospholipase C-γ, Rho Ras homolog gene family member, TrkB tyrosine kinase B receptor

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