BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis

https://doi.org/10.1016/j.pneurobio.2005.06.003Get rights and content

Abstract

Interest in BDNF as an activity-dependent modulator of neuronal structure and function in the adult brain has intensified in recent years. Localization of BDNF-TrkB to glutamate synapses makes this system attractive as a dynamic, activity-dependent regulator of excitatory transmission and plasticity. Despite individual breakthroughs, an integrated understanding of BDNF function in synaptic plasticity is lacking. Here, we attempt to distill current knowledge of the molecular mechanisms and function of BDNF in LTP. BDNF activates distinct mechanisms to regulate the induction, early maintenance, and late maintenance phases of LTP. Evidence from genetic and pharmacological approaches is reviewed and tabulated. The specific contribution of BDNF depends on the stimulus pattern used to induce LTP, which impacts the duration and perhaps the subcellular site of BDNF release. Particular attention is given to the role of BDNF as a trigger for protein synthesis-dependent late phase LTP—a process referred to as synaptic consolidation. Recent experiments suggest that BDNF activates synaptic consolidation through transcription and rapid dendritic trafficking of mRNA encoded by the immediate early gene, Arc. A model is proposed in which BDNF signaling at glutamate synapses drives the translation of newly transported (Arc) and locally stored (i.e., αCaMKII) mRNA in dendrites. In this model BDNF tags synapses for mRNA capture, while Arc translation defines a critical window for synaptic consolidation. The biochemical mechanisms by which BDNF regulates local translation are also discussed. Elucidation of these mechanisms should shed light on a range of adaptive brain responses including memory and mood resilience.

Introduction

The neurotrophin family of signaling proteins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5, is crucially involved in regulating the survival and differentiation of neuronal populations during development (Levi Montalcini, 1987, Davies, 1994, Lewin and Barde, 1996). In addition to these well-established functions in development, a large body of work suggests that neurotrophins continue to shape neuronal structure and function throughout life (Castren et al., 1992, Schnell et al., 1994, Thoenen, 1995, Bonhoeffer, 1996, Prakash et al., 1996, Cabelli et al., 1997, Alsina et al., 2001, Maffei, 2002, Bolanos and Nestler, 2004, Duman, 2004, Tuszynski and Blesch, 2004). While neurotrophins traditionally were thought to operate on a time scale of days and weeks, rapid effects have now been demonstrated on a host of cellular functions including ion channel activity, neurotransmitter release, and axon pathfinding (Song and Poo, 1999, Schinder and Poo, 2000, Kovalchuk et al., 2004).

BDNF has emerged a major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS. This unique role within the neurotrophin family fits with the widespread distribution of BDNF and the co-localization of BDNF and its receptor, TrkB, at glutamate synapses. The versatility of BDNF is emphasized by its contribution to a range of adaptive neuronal responses including long-term potentiation (LTP), long-term depression (LTD), certain forms of short-term synaptic plasticity, as well as homeostatic regulation of intrinsic neuronal excitability (Desai et al., 1999, Asztely et al., 2000, Ikegaya et al., 2002, Maffei, 2002). Here, we focus on the molecular mechanisms and functions of BDNF in LTP in the hippocampus. The hippocampus is the only structure in which these mechanisms have been explored in any detail in the adult brain. Despite individual breakthroughs in recent years, the results often appear contradictory and an integrated understanding of BDNF function in synaptic plasticity is lacking. The role of BDNF in visual cortical plasticity is covered in several recent papers and will not be discussed here (Akaneya et al., 1996, Akaneya et al., 1997, Kinoshita et al., 1999, Kumura et al., 2000, Sermasi et al., 2000, Bartoletti et al., 2002, Ikegaya et al., 2002, Maffei, 2002, Jiang et al., 2003).

The review has three goals. First, we will critically evaluate the literature, dividing the actions of BDNF into three discrete mechanisms (permissive, acute instructive, and delayed instructive). Second, we will elaborate on recent studies suggesting that BDNF drives the formation of stable, protein synthesis-dependent LTP—a process referred to as synaptic consolidation. A working model for synaptic consolidation based on induction of the immediate early gene Arc/Arg3.1 and local regulation of dendritic protein synthesis, is proposed. Third, we aim to integrate current views of BDNF function in synaptic plasticity while pointing to major gaps in the field.

Section snippets

LTP: induction switch, consolidation process

Synaptic plasticity can be defined as an experience-dependent change in synaptic strength (Bliss and Collingridge, 1993). Lasting changes in synaptic strength are almost certainly important in information storage during memory formation (Morris, 2003), yet this traditional view is changing as roles for synaptic plasticity in other adaptive responses including mood stability, drug addiction, and chronic pain are starting to unfold (Malenka and Bear, 2004). LTP is typically induced by

Unique properties of BDNF-TrkB signaling system

Neurotrophins activate one or more receptor tyrosine kinases of the tropomyosin-related kinase (Trk) family (Kaplan and Miller, 2000, Patapoutian and Reichardt, 2001). NGF binds preferentially to TrkA, BDNF and NT-4 to TrkB, and NT-3 to Trk C. In addition to Trk receptors, all neurotrophins bind to the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor superfamily. The role of p75NTR is slowly beginning to emerge (Dechant and Barde, 1997, Gentry et al., 2004, Teng and

BDNF has multiple, distinct functions in LTP

A variety of genetic and pharmacological approaches are being used to probe BDNF function. K252a,1 a non-specific inhibitor of receptor tyrosine kinases, has been used widely in verifying Trk-mediated effects. In recent years more specific pharmacological and genetic approaches have become available. Relatively rapid inhibition of signaling can be achieved using antibodies raised against

Insights from BDNF-induced LTP

Lohof et al. (1993) were the first to show neurotrophin-evoked increases in synaptic transmission. This original observation at the frog nerve-muscle synapse was followed by a flurry of studies on the effects of exogenously applied neurotrophins on hippocampal synaptic transmission (Knipper et al., 1994). The response to exogenous BDNF application in the hippocampus appears to be a function of the preparation used (cell culture, slice, whole animal) as well as the method and duration of

BDNF, dendritic protein synthesis, and translation control

Local protein synthesis has been demonstrated in dendritic processes of mature neurons (Feig and Lipton, 1993, Casadio et al., 1999, Wu et al., 1998, Kacharmina et al., 2000, Pierce et al., 2000, Aakalu et al., 2001, Eberwine et al., 2001, Ju et al., 2004). The foundations of compartmental protein synthesis have been elegantly illustrated in oocyte maturation, early embryogenesis, and myelinization in oligodendrocytes (Carson et al., 1998, Bashirullah et al., 1999, Bashirullah et al., 2001, de

Presynaptic mechanisms and retrograde nuclear signaling

LTP involves coordinate pre- and postsynaptic modifications, as synapses increase in size. The discussion of Arc and dendritic protein synthesis emphasizes postsynaptic mechanisms of BDNF-TrkB signaling in the induction and expression of LTP. However, BDNF also acutely enhances glutamate release from synaptosomes and transiently enhances presynaptic transmission (Lessmann and Heumann, 1998, Jovanovic et al., 2000, Gooney and Lynch, 2001). Does BDNF also have an instructive presynaptic role in

The BDNF hypothesis of synaptic consolidation

Fig. 7 collates recent findings into a working hypothesis of BDNF action in the development of late phase LTP. Based on in vitro studies, we suggest that BDNF is released postsynaptically in response to HFS-induced activation of NMDARs. HFS also results in translocation of αCaMKII mRNA (and presumably other mRNAs) and polyribosomes from sites of storage in dendrites to sites of translation in or near spines.4

BDNF and synaptic tagging

Frey and Morris (1997) have suggested that HFS sets a synaptic tag that allows the capture of proteins involved in late LTP. In their experimental paradigm two convergent inputs to CA1 pyramidal cell dendrites were stimulated. Input 1 received strong HFS leading to protein synthesis-dependent late LTP. They found that weak HFS applied to input 2, which normally gives only early LTP, induced late LTP when applied within the first 3 h after stimulation of input 1. Importantly, development of

Stimulation patterns and BDNF release revisited

The role of BDNF in LTP has been studied using a variety of experimental approaches and different stimulation patterns (summarized in Table 1, Table 2, Table 3). It is obvious that BDNF has multiple actions in LTP and that these actions are a function of stimulation pattern. There are a number of facts that need to be reconciled. First, early LTP induced by TBS is inhibited by acute pharmacological blockers of BDNF/TrkB, while the same inhibitors have no effect on early LTP induced by cluster

Truncated TrkB and spatially restricted signaling: source of controversy?

Diffusion of BDNF appears to be restricted by binding to non-catalytic, truncated TrkB (TrkB.T1) receptors. These receptors are expressed on dendritic shafts and glial processes and highly upregulated during development (Anderson et al., 1995, Biffo et al., 1995, Eide et al., 1996, Drake et al., 1999, Rose et al., 2003). In organotypic visual cortex slices release of BDNF from a point source (single-cell) produces spatially restricted (within 4.5 μm) effects on dendritic outgrowth, suggesting

On the roles of NGF, NT-3, and NT-4

The septo-hippocampal cholinergic system is important for generation of the theta rhythm, for spatial memory function, and modulation of LTP (Pavlides et al., 1988, Buzsaki, 2002, Frey et al., 2003). NGF synthesized in the hippocampus provides trophic support for the cholinergic input, at least under conditions of impaired function or injury (DiStefano et al., 1992, Ehlers et al., 1995, Riccio et al., 1997, Blesch et al., 2001). In addition to these classic trophic actions NGF is capable of

Future perspectives and implications

Many basic issues such as the exact sites of neurotrophin release and the spatial distribution and dynamics of receptor (TrkB and p75NTR) activation are still unclear, particularly in the context of adult synaptic signaling. Current evidence suggests that BDNF signals bidirectionally at glutamate synapses where it triggers events on a time scale from milliseconds to hours. Research in the past decade has come a long way in dissecting the mechanisms of BDNF action into its component parts:

Acknowledgements

Funded by the European Union Biotechnology program (BIO4-CT98-0333) and the Norwegian Research Council.

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