BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis
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.
References (319)
- et al.
Dynamic visualization of local protein synthesis in hippocampal neurons
Neuron
(2001) - et al.
Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory
Cell
(1997) - et al.
Metaplasticity: the plasticity of synaptic plasticity
Trends Neurosci.
(1996) - et al.
Correlations between immediate early gene induction and the persistence of long-term potentiation
Neuroscience
(1993) - et al.
The depolarisation-induced release of [125I]BDNF from brain tissue
Brain Res.
(1996) - et al.
The persistence of long-term memory: a molecular approach to self-sustaining changes in learning-induced synaptic growth
Neuron
(2004) - et al.
BDNF and epilepsy: too much of a good thing?
Trends Neurosci.
(2001) - et al.
Localization of cellular storage compartments and sites of constitutive and activity-dependent release of nerve growth factor (NGF) in primary cultures of hippocampal neurons
Mol. Cell. Neurosci.
(1996) Neurotrophins and activity-dependent development of the neocortex
Curr. Opin. Neurobiol.
(1996)- et al.
Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation
Neuron
(2000)
BDNF-dependent enhancement of exocytosis in cultured cortical neurons requires translation but not transcription
Brain Res.
Opioid receptor dependent long-term potentiation: peptidergic regulation of synaptic plasticity in the hippocampus [see comments]
Neurochem. Int.
Synaptic plasticity in the hippocampus is modulated by behavioral state
Brain Res.
AMPA receptor trafficking at excitatory synapses
Neuron
Opioid receptor-dependent long-term potentiation at the lateral perforant path-CA3 synapse in rat hippocampus
Brain Res. Bull.
Theta oscillations in the hippocampus
Neuron
Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns
Neuron
RNA trafficking in myelinating cells
Curr. Opin. Neurobiol.
A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis
Cell
Neurotrophins: to cleave or not to cleave
Neuron
Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step
Neuroscience
Neurotrophic factors: Neurotrophin autocrine loops
Curr. Biol.
A molecular biological approach to synaptic plasticity and learning
C. R. Acad. Sci. III
Mechanisms of estrogen receptor action in the myocardium. Rapid gene activation via the ERK1/2 pathway and serum response elements
J. Biol. Chem.
Translational control in vertebrate development
Int. Rev. Cytol.
Signalling through the neurotrophin receptor p75NTR
Curr. Opin. Neurobiol.
NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals
Neuron
The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons
Neuron
A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation
J. Biol. Chem.
The coupling of a trkB tyrosine residue to LTP
Trends Neurosci.
In vivo insular cortex LTP induced by brain-derived neurotrophic factor
Brain Res.
Modulation of late phases of long-term potentiation in rat dentate gyrus by stimulation of the medial septum
Neuroscience
Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro
Brain Res.
The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro
Neurosci. Lett.
Asymptotic hippocampal long-term potentiation in rats does not preclude additional potentiation at later phases
Neuroscience
Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo
Neuron
Long-term potentiation involves enhanced synaptic excitation relative to synaptic inhibition in guinea-pig hippocampus
J. Physiol. Lond.
Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor
Proc. Natl. Acad. Sci. U.S.A.
Brain-derived neurotrophic factor blocks long-term depression in rat visual cortex
J. Neurophysiol.
Brain-derived neurotrophic factor enhances long-term potentiation in rat visual cortex
J. Neurosci.
Selective modulation of some forms of schaffer collateral-CA1 synaptic plasticity in mice with a disruption of the CPEB-1 gene
Learn. Mem.
Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity
J. Neurosci.
BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation
Hippocampus
Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF
Nat. Neurosci.
Differential distribution of exogenous BDNF, NGF, and NT-3 in the brain corresponds to the relative abundance and distribution of high-affinity and low-affinity neurotrophin receptors
J. Comp. Neurol.
Localization of brain-derived neurotrophic factor and TrkB receptors to postsynaptic densities of adult rat cerebral cortex
J. Neurosci. Res.
Afferent-specific modulation of short-term synaptic plasticity by neurotrophins in dentate gyrus
Eur. J. Neurosci.
Cytoplasmic polyadenylation element binding protein-dependent protein synthesis is regulated by calcium/calmodulin-dependent protein kinase II
J. Neurosci.
Nerve growth factor rapidly induces prolonged acetylcholine release from cultured basal forebrain neurons: differentiation between neuromodulatory and neurotrophic influences
J. Neurosci.
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