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Review
. 2020 Oct;382(1):15-45.
doi: 10.1007/s00441-020-03253-2. Epub 2020 Sep 18.

The physiology of regulated BDNF release

Tanja Brigadski  1 , Volkmar Leßmann  2   3
Affiliations
Review

The physiology of regulated BDNF release

Tanja Brigadski et al. Cell Tissue Res. 2020 Oct.

Abstract

The neurotrophic factor BDNF is an important regulator for the development of brain circuits, for synaptic and neuronal network plasticity, as well as for neuroregeneration and neuroprotection. Up- and downregulations of BDNF levels in human blood and tissue are associated with, e.g., neurodegenerative, neurological, or even cardiovascular diseases. The changes in BDNF concentration are caused by altered dynamics in BDNF expression and release. To understand the relevance of major variations of BDNF levels, detailed knowledge regarding physiological and pathophysiological stimuli affecting intra- and extracellular BDNF concentration is important. Most work addressing the molecular and cellular regulation of BDNF expression and release have been performed in neuronal preparations. Therefore, this review will summarize the stimuli inducing release of BDNF, as well as molecular mechanisms regulating the efficacy of BDNF release, with a focus on cells originating from the brain. Further, we will discuss the current knowledge about the distinct stimuli eliciting regulated release of BDNF under physiological conditions.

Keywords: BDNF release; Neurotrophins; Secretion.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Schematic illustration of different release sites for BDNF. Release of BDNF takes place from somatic and dendritic compartments (green: ① + ②) and from axonal structures (yellow: ③) of glutamatergic neurons. Presynaptic neuron (yellow) and the postsynaptic glutamatergic neuron (green) are connected via glutamatergic synapses. The postsynaptic neuron additionally receives input from GABAergic interneurons (red). Astrocytic ④ and microglial ⑤ BDNF release has also been described. Recycling of BDNF ⑥ has been observed in neurons and in astrocytes. bAP back-propagating action potential, ER endoplasmic reticulum, GABABR gamma-aminobutyric acid receptor B, IP3-R inositol trisphosphate receptor, mGluR metabotropic glutamate receptor, NaV voltage-gated sodium channel, NMDAR N-methyl d-aspartate receptor, P2XR P2X purinergic receptor, PKC protein Kinase C., PLC phospholipase C, TRPC transient receptor potential channel, VGCC voltage gated calcium channels. Adapted from Brigadski and Leßmann, Neuroforum, 2014.
Fig. 2
Fig. 2
Suggested mechanisms for somatic and dendritic release of BDNF. BDNF release is dependent on extracellular Ca2+-influx (a) and/or intracellular Ca2+-release from internal stores (ER) Ca2+-influx (b). Ca2+-influx from extracellular space is mediated via VGCC and/or NMDAR (a, b). Ca2+ release from ER is mediated via IP3R or RyR (b). Increased burst firing activity, glutamate, or other ligands of GPCR mediate transient intracellular Ca2+-increase important for vesicle exocytosis. AC adenylate cyclase, CAMKII calmodulin-dependent protein kinase II; DAG diacylglycerol, ER endoplasmatic reticulum, IP3 inositol triphosphate, IP3R inositol-3-phosphate receptor, NaV voltage-gated sodium channel, NMDAR N-methyl d-aspartate receptor, PKA protein kinase A, PKC protein kinase C; PLC phospholipase C; RyR ryanodine, VGCC voltage-gated calcium channel. Adapted from Brigadski and Leßmann, Neuroforum, 2014
Fig. 3
Fig. 3
Suggested mechanisms for axonal release of BDNF. BDNF release is dependent on Ca2+-influx from extracellular space via presynaptic NMDAR and intracellular Ca2+-release from internal Ca2+-stores. ER endoplasmic reticulum, IP3R inositol-3-phosphate receptor, NMDAR N-methyl d-aspartate receptor, TBS theta burst stimulation
Fig. 4
Fig. 4
Suggested mechanisms for astrocytic and microglial release of BDNF. Glial BDNF release is dependent on GPCR activation and Ca2+-release from internal Ca2+-stores (a) and on Ca2+-influx via P2X-R (b). AC adenylate cyclase, DAG diacylglycerol, ER endoplasmatic reticulum, IP3 inositol triphosphate, IP3R inositol-3-phosphate receptor, p38MAPK p38-mitogen-activated protein kinase; P2XR purinergic P2X receptor, PKA protein kinase A, PLC phospholipase C; TRPC transient receptor potential channel
Fig. 5
Fig. 5
Suggested mechanisms for recycling of BDNF. Endocytosed BDNF is recycled for re-release event in neurons and astrocytes. ER endoplasmatic reticulum, IP3R inositol-3-phosphate receptor, NMDAR N-methyl d-aspartate receptor, TBS theta burst stimulation
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