Elsevier

Neuroscience Research

Volume 65, Issue 1, September 2009, Pages 11-22
Neuroscience Research

Update article
Mechanisms, locations, and kinetics of synaptic BDNF secretion: An update

https://doi.org/10.1016/j.neures.2009.06.004Get rights and content

Abstract

Brain-derived neurotrophic factor (BDNF) and other members of the protein family of neurotrophins have been implicated in a multitude of processes that are important for neuronal development and synaptic plasticity in the rodent central nervous system. In comparison to the wealth of information available with respect to the biological functions of neurotrophins, our knowledge regarding the processes that govern synaptic secretion of neurotrophins is scarce.

Using live cell imaging of GFP-tagged neurotrophins in primary neurons, immunocytochemical detection of endogenous BDNF in fixed cells, and by blocking the action of endogenously released BDNF by means of TrkB receptor bodies in living neurons, several studies in recent years have allowed to better understand the time course and the mechanisms of synaptic secretion of neurotrophins. This review will summarize the current knowledge regarding the intracellular processing of proneurotrophins, the targeting of neurotrophin vesicles to axons and dendrites, and the mechanisms of activity-dependent secretion of BDNF at synapses. Since these processes are known to be cell type dependent, special emphasis is given to observations gained from experiments in primary neurons.

Introduction

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4 (NT-3, NT-4) constitute the protein family of mammalian neurotrophins. They are secreted homodimeric proteins (monomeric size of mature neurotrophins: 119–129 amino acids; molecular weight: approximately 14 kDa) which are synthesized and released from neurons as well as from innervated non-neuronal tissues (i.e., muscles). Neurotrophins are well-known for their supporting action in regulating neuronal development, differentiation, and survival of distinct neuronal populations (Lewin and Barde, 1996). In addition, especially BDNF is known since long to be a crucial mediator of synaptic plasticity in the central nervous system, both, during development and in the adult. Numerous pre- and postsynaptic actions of BDNF have been described for GABAergic as well as glutamatergic synaptic transmission (for recent reviews see e.g., Carvalho et al., 2008, Lu et al., 2008, Bramham and Messaoudi, 2005; Gottmann et al., in press). Many of these synaptic phenomena have been revealed either after unrestricted and chronic (i.e. long-term) depletion of endogenous BDNF, e.g., in BDNF knockout animals, or following equally unrestricted delivery of additional exogenous BDNF to specific brain areas, acute brain slices, or cultured neurons. However, within the last few years it emerged that understanding the mechanisms of BDNF secretion at the subcellular level, and monitoring the synaptic input specific actions of secreted BDNF is of fundamental importance to uncover the role of BDNF in synaptic plasticity in more detail. In this respect it is no longer doubted that BDNF can be secreted from pre- and postsynaptic structures (Kohara et al., 2001, Kojima et al., 2001, Hartmann et al., 2001; for a recent review see Lessmann et al., 2003), leading to spatially restricted synaptic actions of BDNF (Magby et al., 2006, Walz et al., 2006, Amaral and Pozzo-Miller, 2007b, Lang et al., 2007, Tanaka et al., 2008). Whereas these effects have been attributed mainly to the mature form of BDNF (i.e., the fully processed homodimeric protein, with pre- and prodomains cleaved off), increasing evidence suggests that also the precursor, the so-called proBDNF, can be released and may exert distinctly different biological actions than the mature counterpart. However, no matter whether neurotrophins are secreted as pro-versions or as mature proteins, exocytosis of these proteins can take place either via activity-dependent exocytosis from excitable cells bearing secretory granules, or via the constitutive release pathway, which is present in all cell types. The current update article attempts to summarize the recent progress in the fields of cellular synthesis, prodomain cleavage, subcellular targeting, and synaptic secretion of BDNF and other neurotrophins in neurons, and discusses the consequences of these findings for shaping synaptic plasticity. Further, this article will distinguish between axonal (presynaptic) and dendritic (postsynaptic) release of neurotrophins which likely serve different cellular effects and almost certainly employ differential molecular mechanisms of secretion. We will focus mainly on data obtained from CNS neurons rather than from cell lines, because previous studies suggested that – when it goes to important details – targeting and secretion in cell lines may differ from the respective processes in neurons (Lessmann et al., 2003).

Section snippets

Synthesis, cleavage, and targeting of BDNF and other neurotrophins in central neurons

NTs, like other neuropeptides, are synthesized as pre-proproteins into the ER. The pre-domain is cleaved off immediately, yielding so-called proproteins which can undergo further posttranslational modifications on their way through Golgi apparatus and trans-Golgi network (TGN), to finally end up in secretory vesicles. Two separate types of secretion pathways exist: (i) the regulated pathway, employing Ca2+-dependent exocytosis of secretory granules, and (ii) the constitutive pathway, which

The role of proBDNF and other proneurotrophins

As mentioned in Section 2.1, concepts assuming that pro-domains are just an extension to guide sorting and targeting of mature NTs can no longer be judged valid. Thus, this chapter will consider the targeting, secretion, and possible functions of proneurotrophins.

Location of BDNF secretion: targeting to axons and dendrites

For a better understanding of the role of BDNF in synaptic plasticity, the question arises where in the cell BDNF release can take place. Because of the low level of BDNF expression in most neuronal tissues, unequivocal evidence regarding the subcellular localization of the small amounts of endogenous BDNF in neuronal processes is still lacking. Consequently, the question whether endogenously expressed BDNF is preferentially located in axons or dendrites, or whether release of endogenous BDNF

Acknowledgements

This work was funded by grants to V.L. from the DFG (SFB 779 TP B6, LE 1020/2-1), the Schram Stiftung, and the Stiftung Rheinland-Pfalz für Innovation.

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