Progress in Neurobiology 76 (2005) 99–125

www.elsevier.com/locate/pneurobio

BDNF function in adult synaptic plasticity:

The synaptic consolidation hypothesis
Clive R. Bramham *, Elhoucine Messaoudi
Department of Biomedicine, Bergen Mental Health Research Center, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway

Received 24 February 2005; received in revised form 9 May 2005; accepted 16 June 2005

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., aCaMKII)
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.
# 2005 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2. LTP: induction switch, consolidation process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
3. Unique properties of BDNF-TrkB signaling system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
4. BDNF has multiple, distinct functions in LTP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
4.1. Permissive: setting the stage for activity-dependent synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Abbreviations: ACD, actinomycin D; AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor; Arc, activity-regulated
cytoskeleton-associated protein; Arg, activity-regulated gene; BDNF, brain-derived neurotrophic factor; BDNF-LTP, brain-derived neurotrophic factor-
induced long-term potentiation; CA, cornu ammonis; CaMKII, calcium/calmodulin-dependent protein kinase II; CPEB, cytoplasmic polyadenylation binding
protein; CRE, calcium/cyclic AMP responsive element; Cre, cyclization recombination; CREB, calcium/cyclic AMP responsive element binding protein;
eEF2, eukaryotic elongation factor-2; eIF4E, eukaryotic initiation factor 4E; 4E-BP, eIF4E binding protein; EPSP, excitatory postsynaptic potential; ERK,
extracellular signal-regulated protein kinase; GFP, green fluorescent protein; HFS, high-frequency stimulation; IEG, immediate early gene; IPSP, inhibitory
postsynaptic potential; LTD, long-term depression; LTP, long-term potentiation; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase;
MEK, mitogen and extracellular signal regulated protein kinase; mGluR, metabotropic glutamate receptor; Mnk1, MAPK integrating kinase 1; mTOR,
mammalian target of rapamycin; NGF, nerve growth factor; NMDAR, N-methyl-D-aspartate (NMDA) receptor; NT-3, neurotrophin-3; PI3K, phosphatidy-
linositol-3-OH kinase; PKA, cyclic AMP-dependent protein kinase; PLC, phospholipase C; PSD, postsynaptic density; Trk, tropomyosin-related receptor
kinase; TRP, transient receptor potential; UTR, untranslated region
* Corresponding author. Tel.: +47 55 58 60 32; fax: +47 55 58 64 10.
E-mail address: clive.bramham@biomed.uib.no (C.R. Bramham).

0301-0082/$ – see front matter # 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2005.06.003
100 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125

4.2. Instructive: induction and early LTP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

4.2.1. Multiple forms of early LTP, differential contributions of BDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4.3. Instructive: late LTP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
5. Insights from BDNF-induced LTP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
5.1. Some basic properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
5.2. BDNF-LTP is occluded during late phase LTP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.3. BDNF-LTP induction requires rapid ERK activation and de novo gene expression . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.4. BDNF triggers Arc-dependent synaptic consolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
6. BDNF, dendritic protein synthesis, and translation control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
7. Presynaptic mechanisms and retrograde nuclear signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
8. The BDNF hypothesis of synaptic consolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
9. BDNF and synaptic tagging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
10. Stimulation patterns and BDNF release revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
11. Truncated TrkB and spatially restricted signaling: source of controversy?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
12. On the roles of NGF, NT-3, and NT-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
13. Future perspectives and implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

1. Introduction integrated understanding of BDNF function in synaptic

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 differentia-
tion 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 path-
finding (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 depres-
sion (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
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, 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.
2. LTP: induction switch, consolidation process
Synaptic plasticity can be defined as an experience-
dependent change in synaptic strength (Bliss and Collin-
gridge, 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 high-frequency
stimulation (HFS) of excitatory input leading to rapid
elevation of calcium in postsynaptic dendritic spines. At
most excitatory synapses this critical calcium influx is
provided by activation of N-methyl-D-aspartate (NMDA)
type glutamate receptors, with contributions from voltage-
gated calcium channels and mobilization of calcium from
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
intracellular stores. The rest of LTP, which can last for weeks
and months, is largely unaccounted for. It is widely accepted
that maintenance of LTP involves at least two phases,
dubbed early and late. Early LTP (lasting some 1–2 h)
requires covalent modification of existing proteins and
protein trafficking at synapses, but not new protein synthesis
(Bliss and Collingridge, 1993; Lisman et al., 2002; Malinow
and Malenka, 2002; Malenka and Bear, 2004). Development
of late LTP, like long-term memory, depends on de novo
mRNA and protein synthesis (Frey et al., 1988, 1996; Otani
and Abraham, 1989; Matthies et al., 1990; Nguyen et al.,
1994; Nguyen and Kandel, 1996; Davis et al., 2000;
Raymond et al., 2000; Kandel, 2001; Kelleher et al., 2004b).
LTP is associated with both rapid (minutes) and more
delayed (hours or days) changes in gene expression (Davis
and Laroche, 1998). Only the rapid mechanisms have been
studied in any detail. The early window of gene expression
occurring during the first 60 min or so after HFS is
associated with activation of several constitutively expressed
transcription factors, including cyclic-AMP/calcium respon-
sive-element binding protein (CREB) and Elk-1, leading to
enhanced transcription of a functionally diverse group of
immediate early genes (IEGs). Numerous protein kinases
are involved in this transcriptional regulation. Critical roles
of cyclic-AMP dependent protein kinase (PKA) and
extracellular-signal regulated kinase (ERK) acting through
phosphorylation of CREB have been demonstrated (Impey
et al., 1996, 1998; Abel et al., 1997; English and Sweatt,
1997; Davis et al., 2000; Rosenblum et al., 2002). The notion
of protein synthesis-dependent consolidation is borne out in
various forms of long-term synaptic plasticity and memory
consolidation from flies to man (Kandel, 2001). By analogy
to memory consolidation, synaptic consolidation refers to
protein synthesis-dependent strengthening of synaptic
transmission.
The NMDA receptor is a calcium gate, exquisitely
designed to detect coincident pre- and postsynaptic activity.
This simple molecular switch arises from the voltage-
dependent properties of the NMDAR channel. The ensuing
early LTP is labile and reversible, for instance, by protein
dephosphorylation and other mechanisms of depotentiation
(O’Dell and Kandel, 1994; Staubli and Chun, 1996). In
contrast to the switch-like control of LTP induction, synaptic
consolidation involves a protracted and energy-expensive
synthesis of proteins, leading to a more stable and committed
state of the synapse. Rather than being dictated slavishly by
the LTP induction event, synaptic consolidation is likely to be
a highly regulated process with its own set of controls.
Control mechanisms may exist from the molecular level
to the neural systems level. Modulatory transmitters such as
norepinephrine, serotonin, dopamine, and acetylcholine are
all implicated in modulation of LTP induction or main-
tenance (Stanton and Sarvey, 1985a, 1985b; Bramham and
Srebro, 1989; Frey et al., 1991; Bramham et al., 1997;
Swanson-Park et al., 1999; Graves et al., 2001; Kulla and
Manahan-Vaughan, 2002; Straube and Frey, 2003; Harley
101
et al., 2004). These extrinsic inputs typically have diffuse,
global patterns of innervation, and the neurotransmitters
communicate through spatially dispersed, volume transmis-
sion. Neuronal firing activity in these systems is a function of
the animal’s behavioral or attentional state, with changes in
activity dictating the functional modes of networks (i.e.,
local rhythmic activity, population discharges and synchro-
nization, timing of synaptic events, frequency and duration
of action potential firing), while setting the biochemical tone
of target neurons. The classical modulatory transmitters can
affect gene expression through effects on PKA and CREB
activity. Acetylcholine and dopamine have also been
implicated in regulation of protein synthesis in dendrites
(Feig and Lipton, 1993). However, these extrinsically
controlled, state-dependent systems are not designed to
mediate protein synthesis-dependent consolidation at the
glutamate synapse. More direct, spatially restricted mechan-
isms are likely to exist. As discussed below, the BDNF/TrkB
is ideally positioned to mediate synaptic consolidation,
acting in tandem with glutamate at excitatory synapses.
3. 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 super-
family. The role of p75NTR is slowly beginning to emerge
(Dechant and Barde, 1997; Gentry et al., 2004; Teng and
Hempstead, 2004). One important function may be
facilitation of Trk activation, either by presenting the
neurotrophin to Trks or by inducing a favorable conforma-
tional change in the receptor (Chao and Bothwell, 2002).
There is also evidence that pro-neurotrophins, including pro-
BDNF, is released and preferentially activates p75NTR (Lu,
2003). Ligand binding to Trk leads to autophosphorylation
of tyrosine residues within the intracellular domains of the
receptor, creating docking sites for second messengers. The
adaptor proteins Shc and FRS-2 bind to a common docking
site coupling to activation of the Ras-raf-ERK cascade and
the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway.
Docking of phospholipase Cg (PLCg) to a separate site leads
to production of diacylglycerol, a transient activator of
protein kinase C (PKC), and inositol trisphosphate (IP3),
which mobilizes intracellular calcium (Lessmann et al.,
2003; Amaral and Pozzo-Miller, 2005). Regulation of gene
expression through these pathways underlies the well-
established role of neurotrophins in neuronal differentiation,
survival and outgrowth during development.
Functional diversity within the neurotrophin family is
suggested by the distinct anatomical distributions of each
102 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
neurotrophin/Trk receptor pair (Kokaia et al., 1993; Miranda
et al., 1993; Schmidt Kastner et al., 1996; Conner et al.,
1997; Tanaka et al., 1997; Yan et al., 1997). In the
hippocampus, NGF is expressed in populations of principal
neurons (granule cells and pyramidal cells) while TrkA
receptors are located on cholinergic fibers projecting from
the medial septum/diagonal band, consistent with a
specialized function for NGF in modulating septo-hippo-
campal function (Blesch et al., 2001). In contrast, BDNF and
NT-3 and their respective Trk receptors are expressed on
principal neurons and certain types of interneurons,
implying extensive signaling within the intrinsic hippo-
campal network. NT-3 has a patchy distribution in the
hippocampus, being expressed mainly in granule cells and
CA2 pyramidal cells. Of all the neurotrophins, BDNF/TrkB
is the only signaling system exhibiting widespread
distribution across the subregions of the hippocampus and
the adult forebrain.
BDNF is synthesized, stored and released from gluta-
matergic neurons (Lessmann et al., 2003). Storage and
activity-dependent release has been demonstrated in
dendrites and axon terminals, but the extent to which pre-
and/or postsynaptic release occurs varies greatly among
CNS pathways. In principal neurons of the hippocampus,
BDNF appears to be stored in dendritic processes in
secretogranin II-positive secretory granules from which it is
released in response to HFS (Blochl and Thoenen, 1996;
Hartmann et al., 2001; Kohara et al., 2001; Balkowiec and
Katz, 2002). Catalytic, signal transducing TrkB receptors
have been localized to pre- and postsynaptically elements of
glutamatergic synapses by immuno-electronmicroscopy
(Drake et al., 1999). Catalytic TrkB receptors are found
in the postsynaptic density (PSD) and TrkB co-immuno-
precipitates with NMDAR complex proteins (Aoki et al.,
2000; Drake et al., 1999; Wu et al., 1996; Husi et al., 2000).
These properties make BDNF attractive as a bidirectional
modulator of excitatory synaptic transmission and plasticity.
In terms of synaptic consolidation, two additional features
must be emphasized: (1) BDNF regulates protein synthesis
through both transcriptional and post-transcriptional
mechanisms, and (2) BDNF is capable of stimulating its
own release, possibly allowing sustained, regenerative
signaling at synaptic sites. These features will be discussed
more later.
4. 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
1
K252a is an indolocarbazole alkaloid isolated from the actinomycete
Nocardiopsis sp. (Kaneko et al., 1997).
become available. Relatively rapid inhibition of signaling
can be achieved using antibodies raised against BDNF or
extracellular epitopes on the TrkB receptor, or by treatment
with neurotrophin-scavenging fusion proteins. The BDNF
scavenger, TrkB-Fc, consists of a TrkB ligand-binding
domain fused to the Fc portion of human immunoglobulin.
TrkB-Fc binds neurotrophins with affinities similar to that of
the intact receptor and can block the effects of exogenously
applied BDNF (Shelton et al., 1995). While antibodies and
scavengers block some of the expected effects of
endogenous BDNF, the efficacy of these large molecules
in blocking TrkB activation in intact tissue in general, and
synaptic regions in particular, has not been studied in any
detail (Shelton et al., 1995; Croll et al., 1998; Binder et al.,
1999). Genetic approaches such as targeted knockout or
conditional gene deletion provide a definitive analysis of
total gene product function. Nonetheless, because these
approaches all involve long periods of gene product
knockdown prior to the LTP experiments, they are of
limited value in unraveling the dynamic aspects of BDNF
transmission. The biochemical and physiological responses
to the exogenous application of BDNF have also been
studied. This line of investigation has proved useful in
elucidating BDNF-specific actions in synaptic transmission
and plasticity, although the physiological relevance of these
effects must always be questioned and compared with
endogenous actions. A summary of the effects of genetic and
pharmacological manipulations of BDNF-TrkB is shown in
Tables 1 and 2, respectively. The effects of exogenous BDNF
application are summarized in Table 3 and will be discussed
separately.
A combination of genetic and pharmacological
approaches has revealed multiple, distinct contributions of
BDNF signaling to LTP. These actions may be classified as
permissive or instructive (Schinder and Poo, 2000).
Permissive refers to effects of BDNF that make synapses
capable of LTP in the first place, but which are not causally
involved in generating LTP. For example, basal (non-
evoked) release of BDNF maintains the presynaptic release
machinery, enabling sustained presynaptic transmission
during HFS (Figurov et al., 1996). In contrast, instructive
refers to BDNF signaling that is initiated in response to HFS
and causally involved in the development of LTP. Evidence
for immediate and more delayed instructive roles of BDNF
has been obtained. Studies supporting each of these roles are
described below. The predicted time course of BDNF release
and mechanism of action is shown in Fig. 1.
The first groundbreaking work was based on analysis of
BDNF knockout mice. Two groups independently reported
impairment of early LTP in mice homozygous or hetero-
zygous for BDNF (Korte et al., 1995; Patterson et al., 1996).
LTP could be rescued by reintroducing BDNF, either by
incubating the slices in BDNF-containing medium or by
adenovirus-mediated transfection of CA1 cells with the
BDNF gene (Korte et al., 1996). These knockout studies set
the stage for dissection of mechanisms using other tools.
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125 103

Table 1
Effect of genetic manipulations of BDNF/TrkB on LTP
Genetic manipulation Stimulation parameters Fatigue Induction E-LTP L-LTP References
a
BDNF ko +/
and
/
2  Tet, cluster ND # # n.a. Patterson et al. (1996)
+/
and
/
3  Tet, cluster ND # # # Korte et al. (1995);
Korte et al. (1998)

/
4  Tet, spaced ND – # # Patterson et al. (2001)
1  TBS ND – ##b ##
+/
2  Tet, cluster " # # ND Pozzo-Miller et al. (1999)

/
"" ## # ND
BDNF conditional deletion
/
(CA3–CA1) 6  TBS cluster ND – # ND Zakharenko et al. (2003)
10  Tet (200 Hz) cluster ND – # ND
3  Tet (50 Hz) cluster ND – – ND

/
(CA1) 6  TBS cluster ND – – ND
10  Tet (200 Hz) cluster ND – – ND
TrkB conditional deletion Hypomorph Global 2  Tet cluster " # # ND Xu et al. (2000)
reduction (fBZ/fBZ) Pairingc n.a. – – ND
trkB-cre CA1-KO 2  Tet cluster " #d # ND
trkB-cre heterozygouse 3  TBS cluster – – # ND Minichiello et al.
trkB-cre homozygous 3  TBS cluster – # ##f # (1999, 2002)
3  Tet cluster ND ND # #
TrkB-tyrosine mutation Shc
/
g 3  TBS cluster – – – – Minichiello et al. (2002)
3  Tet cluster ND – – – Korte et al. (2000)
PLC
/
3  TBS cluster – # # # Minichiello et al. (2002)
3  Tet cluster ND # # #
3  Tet, spaced ND # # #
Truncated TrkB overexpression TrkB.T1 1  TBS ND – – – Saarelainen et al. (2000)
ND = not determined. # = reduction. ## = greater reduction within the same study. n.a. = not applicable. In cases where early LTP is completely abolished,
measurements of late LTP are non-applicable. TBS, theta-burst stimulation. A single session of TBS typically consists of 4-pulses at 100 Hz repeated 10 or more
times at intervals of 200 ms. Tet, Tetanic stimulation consisting of continuous 100 Hz stimulation for 0.5–1 s. Cluster = multiple sessions of stimulation
separated by 30 s or less. Spaced = multiple sessions of stimulation separated by at least 5 min.
All studies refer to changes in the field EPSP slope CA3–CA1 synapses of mouse hippocampal slices.
Fatigue = attentuation of EPSPs to consecutive responses in a stimulus train. Induction = magnitude of the potentiation recorded during the first 3–5 min post-
HFS. Statistics at this time were generally not available in the literature; effects indicated are based on non-overlapping error bars in group time plots. E-
LTP = potentiation between 30 and 90 min post-HFS. L-LTP = potentiation measured at least 2 h post-HFS.
TrkB conditionals: (1) TrkB hypomorph: A mutant trkb allele was designed in which the first coding exon of the TrkB gene is replaced with a TrkB
cDNA unit and flanked by LoxP sites. The allele, termed fBZ/fBZ, is under control of the normal TrkB promoter-enhancer complex. The expression of catalytic
TrkB protein is reduced 24% relative to wildtype but shows a normal anatomical pattern of distribution. (2) CA1-KO: The aCaMKII promoter was used to drive
expression of cre recombinase in the floxed (fBZ mutant) mice referred to above. In the hippocampus this resulted in specific deletion of trkB from CA1
pyramidal cells. In the work of Minichiello and coworkers, aCaMKII-driven Cre-Lox recombination resulted in forebrain-specific deletion of TrkB.
TrkB-tyrosine mutants: Two strains of mice were generated in which the tyrosine (Y) docking sites for PLC (Y816) or shc (Y515) were mutated to
phenylalanine.
Truncated TrkB overexpression: Truncated TrkB.T1 was overexpressed as a dominant negative inhibitor of TrkB activation.
a
Analysis of late phase not applicable as LTP in weight mice lasted only 1.5 h.
b
Decrease in LTP starting approximately 60 min post-TBS.
c
Membrane depolarization to 0 mV was paired with 1 Hz stimulation for 100 s.
d
Reduction in LTP equivalent to that obtained in fbz/fbz mice.
e
Heterozygotes (trkBlox/+; CaMKII-CRE or trkBlox/null).
f
Homozygous cre show greater reduction than heterozygous. TBS-induced and Tet-induced LTP were equally impaired in homozygotes.
g
Similar results obtained in Shc +/
mutants.

Later genetic studies employed spatially restricted inhibition
of BDNF and TrkB gene expression and examined different
forms of LTP (to be discussed) (Minichiello et al., 1999,
2002; Xu et al., 2000; Zakharenko et al., 2003).
4.1. Permissive: setting the stage for activity-dependent
synaptic plasticity
Synaptic fatigue is a reduction in EPSP amplitude obs-
erved in response to consecutive stimuli in a stimulus burst.
Evidence suggests that BDNF modulates LTP indirectly by
inhibiting synaptic fatigue. In the first study to address this
issue Figurov et al. (1996) used TrkB-Fc to sequester
extracellular TrkB ligands in adult rat hippocampal slices.
Inhibition of BDNF signaling enhanced synaptic fatigue and
impaired both the induction and early maintenance of LTP at
CA3–CA1 synapses. Conversely, when BDNF was applied to
hippocampal slices of early postnatal rats, in which
endogenous BDNF levels are low, synaptic fatigue was
attenuated and LTP induction correspondingly facilitated.
104 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125

Table 2
Effect of function blocking BDNF/TrkB antibodies on LTP
Antibody Mode and timing of application Stimulation parameters Fatigue Induction E-LTP L-LTP References
TrkB-Fc Brief perfusion 15 min pre-HFS to 3  Tet spaced ND – – # Kang et al. (1997)
15 min post-HFS
30 to 60 min post-HFS 3  Tet spaced ND n.a. – #
70 to 100 min post-HFS 3  Tet spaced ND n.a. n.a. –
15 min pre-HFS to 15 min post-HFS 1  TBS – ND ND ND
3 h pre-baseline perfusion 1  TBS " # # n.a. Figurov et al. (1996)
Continuous perfusion 3  Tet cluster – – – ND Chen et al. (1999)
3  TBS cluster – # # ND
1 h pre-incubation 1  TBS ND – # # Patterson et al. (1996)
TrkB Ab 2 h pre-incubation Pairinga n.a. n.a. # ND Kang et al. (1997)
1  TBS ND – # n.a.
3  TBS cluster ND – # n.a.
4  Tet cluster ND – – n.a.
3  Tet spaced ND – – #
BDNF Ab Continuous perfusion starting 1 h pre-baseline 3  Tet cluster – – – ND Chen et al. (1999)
3  TBS cluster – # # ND
Perfusion from 10 min post-HFS to end 3  TBS cluster n.a. n.a. – –
of recordingb
Photoactivation of Ab 2 min pre-HFS 3  TBS cluster ND # # for 30 min ND Kossel et al. (2001)
to 2 min post-HFS
During and 2 min post-HFS 3  TBS cluster ND # # for 10 min ND
a
Membrane depolarization to 0 mV was paired with 1 Hz stimulation for 30 s.
b
Ab perfusion started at 10, 30, or 60 min after TBS and continued for the duration of recording (up to 3 h).

Subsequent electrophysiological and biochemical studies
identified a presynaptic locus for BDNF regulation of
synaptic fatigue (Gottschalk et al., 1998). Pozzo-Miller et al.
(1999) demonstrated enhanced synaptic fatigue and impair-
ment of LTP in slices obtained from BDNF knockout mice.
The effects in BDNF mutants correlate with reduced
expression of the synaptic vesicle-associated proteins
synaptobrevin and synaptophysin and a reduction in the
proportion of docked (readily releasable) vesicles in the
active zone. A similar enhancement in synaptic fatigue and
reduction in the expression of synaptic vesicle-associated
proteins is seen in TrkB mutant mice (Martinez et al., 1998;
Xu et al., 2000). Mice in which TrkB receptors are
selectively deleted from postsynaptic neurons at CA3–CA1
synapses exhibit normal synaptic fatigue and intact early
LTP suggesting that these functions are regulated by
presynaptic TrkB signaling (Xu et al., 2000).
BDNF incubation of slices obtained from BDNF
knockouts restores expression of presynaptic proteins and
reverses the effects on synaptic fatigue and LTP. This effect
requires at least 3–4 h of BDNF incubation and involves
transcription-dependent and transcription-independent

Table 3
Effect of exogenous BDNF application on excitatory synaptic transmission in the hippocampus
Preparation Application method Effect on EPSPs Other effects/comments References
Primary hippocampal Incubation Transient increase Lessmann et al. (1994)
cultures (20 min duration) Levine et al. (1995b)
Li et al. (1998)
Acute hippocampal Bath perfusion None Impairs synaptic fatigue & enhances Figurov et al. (1996)
slicea CA3–CA1 synapse LTP induction in P12–13 rats
None Small # evoked IPSCs. Frerking et al. (1998)
High perfusion rates used
Long-lasting increase High perfusion rates required Kang and Schuman (1995)
Kang et al. (1996)
Alarcon et al. (2004)
Bath incubation None Patterson et al. (1996)
Brief (1 s) puff from No lasting effect Induces rapid depolarization. Kafitz et al. (1999)
micropipette Pairing with current injection gives LTP Kovalchuk et al. (2002)
In vivo anesthetized Brief (25 min) Long-lasting increase Messaoudi et al. (1998)
dentate gyrus local infusion Messaoudi et al. (2002)
Ying et al. (2002)
a
CA3–CA1 synapses studied.
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
Fig. 1. Multiple roles of BDNF in hippocampal long-term potentiation. Several lines of evidence from genetic and pharmacological studies suggest three major
actions of BNDF in LTP: permissive, acute instructive, and late instructive. The predicted time course of the BDNF signaling events are shown. See text for
details.
mechanisms (Bradley and Sporns, 1999; Tartaglia et al.,
2001; Thakker-Varia et al., 2001). Significantly, work in
primary hippocampal cultures shows that BDNF incubation
enhances transcription of Rab3a, a small GTP-binding
protein important for trafficking transmitter vesicles to the
active zone (Thakker-Varia et al., 2001). Taken together
these studies suggest that BDNF facilitates frequency-
dependent transmission and LTP induction through regu-
lated synthesis of proteins involved in vesicle trafficking and
neurotransmitter exocytosis. The emergence of this mechan-
ism during early postnatal development critically alters the
burst capability of excitatory synapses. It also raises the
intriguing possibility that LTP induction is influenced by the
prior history of tonic BDNF signaling in the adult brain. This
would be a form of metaplasticity, as discussed by Abraham
and Bear (1996). (For review of the presynaptic actions of
BDNF see Tyler et al., 2002b; Schinder and Poo, 2000).
4.2. Instructive: induction and early LTP
Endogenous BDNF is clearly capable of modulating LTP
through mechanisms that do not involve suppression of
synaptic fatigue. Several studies report suppression of early
LTP in mice with genetically reduced BDNF or TrkB
function in the absence of changes in synaptic fatigue (Korte
et al., 2000; Minichiello et al., 1999, 2002; Zakharenko
et al., 2003). Secondly, acute pharmacological inhibition of
BDNF-TrkB signaling impairs LTP without affecting
synaptic fatigue (Figurov et al., 1996; Kang et al., 1997;
Chen et al., 1999; Kossel et al., 2001; Patterson et al., 2001).
In an elegant study employing photo-induced release of
caged BDNF antibody, Kossel et al. (2001) sought to resolve
rapid actions of BDNF during HFS. Hippocampal slices
were incubated in medium containing caged antibody and
flashes of UV light were applied from 2 min before until
2 min after HFS. LTP was impaired in the period from
immediately after HFS to approximately 30 min thereafter.
105
Although the effects were modest, this work provided direct
evidence for immediate instructive actions of endogenous
BDNF in LTP. Kang et al. (1997) showed that TrkB antibody
blocked LTP induced by pairing low-frequency (1 Hz)
stimulation with sustained depolarization of postsynaptic
CA1 pyramidal cells. Thus, modulation of early LTP by
endogenous BDNF does not strictly require high-frequency
presynaptic activity.
In another important advance BDNF was shown to be a
potent neuroexcitant (Blum and Konnerth, 2005). Using
focal, puff application in acute hippocampal slices,
extremely rapid (millisecond) depolarizations were evoked
by nanomolar concentrations of BDNF (Kafitz et al., 1999).
This rapid depolarization is mediated by a tetrodotoxin-
insensitive voltage-gated sodium channel (Nav 1.9), which is
thought to couple directly to TrkB independently of second
messenger signaling (Blum et al., 2002; Blum and Konnerth,
2005). Kovalchuk et al. (2002) investigated the effect of
exogenous BDNF on HFS-LTP at medial perforant path-
granule cell synapse. BDNF puffed into the synaptic region
induced a sharp rise in calcium levels in the spines and shafts
of granule cells dendrites and a burst of action potentials in
the cell body. BDNF had no effect on synaptic efficacy when
given alone, but triggered LTP when paired with weak HFS.
The timing in the pairing protocol was critical. Potentiation
was obtained when stimulation was given within 1 s of
BDNF application, a time window exactly corresponding to
the time course of the BDNF-induced depolarization. The
effect was abolished by blocking NMDA receptors, voltage-
dependent calcium channels, or by chelation of postsynaptic
calcium. Thus, puffs of BDNF can directly gate LTP
induction through rapid modulation of postsynaptic calcium
influx. The facilitating effect of puffed BDNF meshes with
the rapid instructive effect of endogenous BDNF shown by
Kossel et al. (2001). In future studies it will be important to
determine whether endogenous BDNF modulates Nav 1.9
channels.
106 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
4.2.1. Multiple forms of early LTP, differential
contributions of BDNF
In an intriguing twist the effect of acutely applied
inhibitors on early LTP were shown to depend on the specific
pattern of HFS used for LTP induction. Two main patterns of
HFS have been studied: theta-burst stimulation (TBS) and
tetanus. TBS consists of 10 or more 100 Hz bursts, delivered
at the frequency (5 Hz) of the hippocampal theta rhythm.
The most common tetanus parameter used in the hippo-
campal slice preparation is continuous 100 Hz stimulation
for 0.5–1 s. Studies in which the stimulation patterns have
been compared show that only TBS-LTP is impaired by
acute application of BDNF/TrkB inhibitors (Kang et al.,
1997; Chen et al., 1999).
The work of Zakharenko et al. (2003) has shed light on the
mechanisms involved at CA3–CA1 synapses. In this study
regionally specific transgenic lines were used to condition-
ally delete BDNF from the entire forebrain (e.g., BDNF was
eliminated from both CA3–CA1 neurons) or only from CA1
pyramidal cells. Presynaptic function was investigated using
the activity-dependent fluorescent marker of synaptic vesicle
cycling, FM 1–43. Earlier work using this technique
demonstrated a strong correlation between synaptic trans-
mission and kinetics of FM 1–43 release from synaptic
vesicles (Zakharenko et al., 2001). In the 2003 study,
Zakharenko and coworkers showed selective deficits in TBS-
LTP and presynaptic mechanisms of expression when BDNF
was deleted from both presynaptic and postsynaptic neurons.
When BDNF was eliminated only from postsynaptic neurons
TBS-LTP was normal. Furthermore, the deficit in pre-
synaptic LTP expression was rescued by sindbis viral
infection of BDNF into CA3, but not CA1, pyramidal cells.
Together this work suggests (1) that BDNF is required for
presynaptic expression of LTP in region CA1, and (2) that a
presynaptic source of BDNF is critical for this expression.
However, these studies concentrated on BDNF function in
early LTP—as it turns out, late LTP is another story.
4.3. Instructive: late LTP
Genetic and pharmacological studies both suggest a
critical function for BDNF in late LTP (Kang et al., 1997;
Minichiello et al., 1999, 2002; Patterson et al., 2001). The
first evidence came from studies of BDNF germline
knockout mice (Korte et al., 1995; Patterson et al., 1996).
By focusing on slices with significant early LTP and
monitoring the responses over longer time periods, a deficit
in long-term maintenance of the response was apparent
(Korte et al., 1998). Kandel and coworkers showed that
spaced, but not single, HFS produces stable transcription-
dependent LTP (Huang et al., 1996). BDNF-TrkB con-
tributes to both early and late LTP development under these
conditions, but distinct mechanisms appear to be involved.
For instance, strong stimulus paradigms overcome the deficit
in early LTP, but not late LTP, in TrkB mutant mice
(Minichiello et al., 2002).
Using a spaced HFS protocol, Kang et al. (1997) showed
that TrkB antibody prevented development of late LTP while
leaving early LTP almost completely intact. To examine the
role of BDNF signaling during LTP maintenance the authors
perfused hippocampal slices with TrkB-Fc at different time
points after HFS. Remarkably, LTP was reversed when the
scavenger was applied from 30 to 60 min (but not 70–
100 min) after LTP induction, suggesting that late LTP
depends on a critical period of TrkB signaling after HFS.
This work on endogenous BDNF-TrkB signaling is
complemented by studies showing that brief infusion of
BDNF selectively activates biochemical mechanisms lead-
ing to late phase LTP.
5. 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 (Knip-
per 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 application (Table 3).
BDNF treatment of embryonic or early postnatal
hippocampal neurons results in a transient potentiation
excitatory synaptic transmission lasting 10–20 min follow-
ing washout (Lessmann et al., 1994; Levine et al., 1995a; Li
et al., 1998). In the adult hippocampus, a brief puff of BDNF
induces a calcium transient in spines without affecting
synaptic efficacy (Kovalchuk et al., 2002). In contrast,
application of BDNF for several minutes can trigger a long-
lasting increase in synaptic efficacy dubbed BDNF-induced
LTP (or simply BDNF-LTP). Persistent potentiation was first
shown at CA3–CA1 synapses in response to bath perfusion
of hippocampal slices with BDNF (Kang and Schuman,
1995, 1996). BDNF-LTP was subsequently shown in vivo in
the dentate gyrus, visual cortex, and insular cortex
(Messaoudi et al., 1998; Jiang et al., 2001; Escobar et al.,
2003). Although exogenous NT-3 (but not NGF) elicits long-
lasting potentiation in the CA1 region (Kang and Schuman,
1995), this effect appears to be mediated by TrkB activation
(Ma et al., 1999). Studies of exogenous BDNF-LTP have
helped to elucidate cellular mechanisms of synaptic
plasticity specifically mediated by this neurotrophin. The
discussion below elaborates on recent findings in the dentate
gyrus in urethane-anesthetized rats.
5.1. Some basic properties
BDNF-LTP is induced at medial perforant path-granule
cell synapses in the dentate gyrus by a single, brief (25 min)
infusion of BDNF (Fig. 2a). The infusion site is located
300 mm above the medial perforant path synapse. Field
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
Fig. 2. BDNF-LTP in the dentate gyrus is NMDAR-independent. (a)
BDNF-LTP induced at medial perforant path-granule cell synapses in
urethane-anesthetized rats. The time period of BDNF infusion (2 mg BDNF
in 2 ml; 25 min) is indicated by the hatched bar. Inset shows the position of
infusion cannula and attached recording electrode. (b) HFS applied in the
presence of the NMDA receptor antagonist, CPP, fails to induce LTP, while
BDNF-LTP is readily induced in the same rats. (c) NMDAR blockade does
not affect the amplitude of BDNF-LTP.
EPSPs are significantly elevated 15 min after infusion and
climb to a stable plateau within 2–3 h. The full duration of
BDNF-LTP has not been determined, but it lasts at least 15 h
in anesthetized rats (Messaoudi et al., 1998, 2002; Ying
et al., 2002) and 24 h in freely moving rats (Messaoudi and
Bramham, unpublished). Like LTP, BDNF-LTP is associated
with enhanced EPSP-spike coupling in addition to enhanced
synaptic efficacy (Bliss and Lomo, 1973; Abraham et al.,
1987; Lu et al., 2000; Messaoudi et al., 2002). BDNF is a
relatively large (26 kDa dimer) and sticky protein with
relatively poor tissue perfusion. However, immunocyto-
chemical staining shows that BDNF rapidly penetrates and
clears from the dentate gyrus within 1 h after infusion
(Messaoudi et al., 2002).
BDNF activation of TrkB receptors is implicated in
epileptogenesis (Binder et al., 2001; He et al., 2004). BDNF
and other neurotrophins can also modulate GABAergic
transmission (Tanaka et al., 1997; Frerking et al., 1998)
Recently, Scharfman et al. (2003) showed that chronic (2
weeks) application of BDNF is associated with spontaneous
seizures and mossy fiber sprouting in the dentate hilar
region. In hippocampal slice-cultures picrotoxin-induced
seizures leads to release of endogenous BDNF, axonal
branching of mossy fibers, and development of hyperexci-
table reentrant circuits in the dentate gyrus (Koyama et al.,
2004). In contrast to these pathophysiological effects
BDNF-LTP is not accompanied by changes in recurrent
GABAergic inhibition, hyperexcitability (e.g., multiple
107
population spikes) or epileptiform spiking (Messaoudi
et al., 1998). It is nonetheless possible that BDNF-LTP at
glutamate synapses contributes to seizure pathogenesis.
The fact that BDNF is capable of acutely increasing
glutamate release raises the possibility that BDNF induces
potentiation only indirectly through NMDAR-dependent
potentiation. However, BDNF-LTP at CA3–CA1 synapses
in hippocampal slices does not require NMDAR activation
(Kang and Schuman, 1995). To address this issue in vivo,
BDNF was infused into the dentate gyrus following systemic
administration of a competitive NMDAR antagonist
(Messaoudi et al., 2002). While blocking NMDA receptors
abolished HFS-LTP, infusion of BDNF in the same animals
induced robust potentiation (Fig. 2b and c). Interestingly,
release of BDNF-GFP from hippocampal neurons in
response to HFS depends on NMDAR and AMPAR
activation (Hartmann et al., 2001). Thus it may be that
exogenous application of BDNF bypasses this initial release
event.
5.2. BDNF-LTP is occluded during late phase LTP
A crucial issue is whether exogenous BDNF reflects the
physiological actions of endogenous BDNF. If two forms of
LTP utilize a common mechanism of expression the
generation of one should occlude (inhibit) the other.
Messaoudi et al. (2002) examined the effect of BDNF
infusion at time points corresponding to early and late LTP
(Fig. 3). BDNF applied during early LTP induced robust
potentiation indicating a distinct mechanism of expression at
this time. Strikingly, complete occlusion was observed when
BDNF was applied during late LTP. Occlusion also occurs in
the other direction; thus prior induction of BDNF-LTP
occludes induction of late, but not early, HFS-LTP at CA3–
CA1 synapses (Kang et al., 1997). This time-dependent
pattern of occlusion implies that exogenous BDNF
specifically activates mechanisms common to late LTP. It
also suggests a rapid switch in the mechanism of expression
between early and late phase LTP. This work is in agreement
with a previous occlusion study in which early LTP could be
re-induced at 4 h, but not 1 h, after HFS (Frey et al., 1995).
5.3. BDNF-LTP induction requires rapid ERK
activation and de novo gene expression
Ying et al. (2002) examined the role of ERK signaling in
BDNF-induced LTP. Local infusion of the MEK (MAPK, or
ERK, kinase) inhibitors PD98059 and U0126 completely
abolished BDNF-LTP induction but had no effect on
established BDNF-LTP (Fig. 4). Immunoblot analysis
performed in homogenates obtained from microdissected
dentate gyrus confirmed rapid phosphorylation of ERK.
Treatment with MEK inhibitors blocked this activation in
parallel with BDNF-LTP. Thus, MEK-ERK activation is
required for the induction, but not the maintenance, of
BDNF-LTP. Furthermore, BDNF-LTP induction is tran-
108 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125

Fig. 3. BDNF-LTP is occluded by late phase, but not early phase, HFS-LTP. (a) LTP of the fEPSP was induced by three sessions of HFS (400 Hz, eight pulses,
repeated four times). After 30 min of recording the stimulus intensity was lowered to reset the response to baseline. HFS at this time produced no further
increase, demonstrating saturation of early HFS-LTP. BDNF infusion (hatched bar) induced normal BDNF-LTP. (b) HFS-LTP in this group was followed for
240 min. BDNF infusion at this time had no effect, demonstrating occlusion with late phase LTP. Values are group means (S.E.M.) expressed in percent of
baseline. Adapted from Messaoudi et al. (2002).

scription-dependent and associated with ERK-dependent
phosphorylation of CREB on serine-133, which is required
for CRE-driven gene expression.
5.4. BDNF triggers Arc-dependent synaptic
consolidation
A miscellany of IEGs encoding transcription factor and
non-transcription factor proteins are induced following LTP
induction (Cole et al., 1989; Wisden et al., 1990; Abraham
et al., 1993; Meberg et al., 1993; Qian et al., 1993; Link
et al., 1995; Lyford et al., 1995; Williams et al., 1995; Tsui
et al., 1996; Lanahan et al., 1997). Transcription factor IEGs
such as zif268 (a.k.a. egr-1, ngfi-a, krox24) and nurr1
regulate late response genes, although the targets of these
genes have yet to be identified. The non-transcription factor
genes encode synaptic proteins such as activity-regulated
cytoskeleton-associated protein (Arc; a.k.a. activity-regu-
lated gene, Arg3.1) and Homer1a, as well as secreted
proteins such as tissue plasminogen activator, neuronal
activity-regulated pentraxin, and BDNF itself.
Zif268 and Arc are both implicated in LTP maintenance
and memory consolidation. Mice carrying a germline
knockout of the zif268 gene have impaired late LTP (1 day
post-HFS) and show deficits in several hippocampal-
dependent memory tasks (Jones et al., 2001). Arc is the
only mRNA known to rapidly traffic to dendritic processes
following LTP induction. Arc protein co-immunoprecipitates
with F-actin and can be found in the PSD, but its cellular
function is undefined. Using intrahippocampal injection of
Arc antisense (AS) oligodeoxynucleotides (ODN), Guzowski
et al. (2000) showed that Arc is required for consolidation,

Fig. 4. BDNF-LTP induction, but not maintenance, requires ERK signaling. (a) BDNF infusion (open bar) induces LTP of medial perforant path-evoked
fEPSPs. Infusion of the MEK inhibitor U0126 (30 mM) into the dentate gyrus immediately before (black bar) and during BDNF infusion (hatched bar) abolished
BDNF-LTP induction. Control BDNF infusion (open bar). (b) The same application of MEK inhibitor 2 h after BDNF infusion had no effect. (c) Rapid ERK
activation is seen in the dentate gyrus (DG) but not in the CA1 and CA3 regions of the hippocampus. The bar graph shows changes in phospho-ERK
immunoreactivity in homogenates of BDNF-treated DG relative to contralateral control. U0126 blocked ERK activation in parallel with BDNF-LTP. Adapted
from Ying et al. (2002).
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
but not acquisition, of hippocampal-dependent learning
tasks. More preliminary work suggested that LTP main-
tenance might be similarly impaired. Rats treated with Arc
AS prior to HFS showed clear LTP lasting several days, but
the potentiation was weaker and decayed sooner than in
control-infused rats. However, these LTP experiments are
difficult to interpret in the absence of data collected from the
baseline period before and after administration of ODN.
Ying et al. (2002) examined expression of Arc and zif268
following BDNF-LTP (Fig. 5). Arc mRNA and protein were
both sharply upregulated, whereas zif268 expression was
unchanged at the same time points. In situ hybridization
revealed enhanced Arc expression across the granule cell
layer and molecular layer of the dentate gyrus, indicating
delivery of transcripts to dendritic processes. Upregulation
of Arc protein, like BDNF-LTP, required ERK signaling and
new transcription (Messaoudi et al., 2002; Ying et al., 2002).
Fig. 5. BDNF induces selective upregulation of Arc mRNA and protein
expression. (a) Autoradiographs of in situ hybridization signals showing
upregulation of Arc mRNA levels in granule cells somata and dendrites 2 h
after BDNF-LTP induction. (b) Enhancement in Arc protein expression is
specific to the infused dentate gyrus and blocked by the transcription-
inhibitor actinomycin D (ACD). *Significantly different from BDNF con-
trol. Zif268 mRNA and protein levels were unchanged. (c) Representative
Western blots. Adapted from Messaoudi et al. (2002) and Ying et al. (2002).
109
Taken together the work in the dentate gyrus suggests that
BDNF triggers synaptic consolidation (late LTP) through
rapid activation of MEK-ERK coupled to ERK-dependent
activation of CREB and upregulation of Arc. BDNF can
nonetheless be expected to regulate a number of genes
having no role or only a subsidiary role in LTP. A possible
causal role for Arc in BDNF-LTP was recently investigated
using local infusion of Arc AS ODN (Messaoudi et al., 2004,
2005). Treatment with Arc AS prior to BDNF infusion had
no effect on baseline synaptic transmission but abolished
BDNF-LTP and the associated upregulation of Arc protein,
indicating a requirement for Arc induction. The effects of
Arc AS on the maintenance of the potentiation were also
studied. While previous work showed that U0126 and ACD
have no effect when applied 2 h after BDNF, Arc antisense
applied at the same time point led to a rapid and complete
reversal of BDNF-LTP. This reversal was coupled to a rapid
reduction in Arc protein expression in the dentate gyrus,
while expression of b-actin, PSD-95, and aCaMKII were
unchanged. Treatment with Arc AS 4 h after BDNF infusion
had no effect. Furthermore, the same time-dependent
sensitivity to Arc AS was observed during the maintenance
phase of HFS-LTP. It was concluded that Arc synthesis is
necessary both for development of BDNF-induced synaptic
strengthening and its time-dependent consolidation. The
rapid knockdown of Arc protein indicates a rapid turnover
such that sustained translation of Arc during a critical time
window is necessary to complete synaptic consolidation.
Changes in Arc protein levels following LTP induction
have recently been examined by immuno-electronmicro-
scopy (Moga et al., 2004; Rodriguez et al., 2005). The time
course of Arc protein elevation in dendritic spines of medial
perforant path-granule cell synapses (up at 2 h, down at 4 h)
(Rodriguez et al., 2005) matches the critical period of
synaptic consolidation shown using Arc antisense. Although
Arc mRNA is transported throughout the dendritic tree
following LTP induction, ultrastructural localization of the
protein indicates more specific increases of Arc expression
in activated dendritic spines, emphasizing the importance of
local translation2 (Steward and Worley, 2001a; Moga et al.,
2004; Rodriguez et al., 2005).
Since the increase in Arc protein seen during BDNF-LTP
is transcription-dependent, it must stem predominantly from
translation of new mRNA rather than pre-existing mRNA.
The delivery of newly induced Arc to synaptic sites may go
hand-in-hand with the activation of local translation by
2
The distribution of Arc mRNA and protein in the dentate gyrus mole-
cular layer depends on the duration of the HFS protocol used. At the light
microscopic level, expression of mRNA and protein follow the same
pattern. LTP induced by conventional short trains of HFS (400 Hz) is
associated with elevations in Arc mRNA and protein throughout the
dendritic field. No band is evident in the middle molecular layer corre-
sponding in the medial perforant path synapses. However, when the same
stimulation pattern is continued for 15 min or more a band of Arc mRNA
and protein appears (Steward and Worley, 2001b). The ultrastructural study
of Rodriguez et al. (2005) suggests that local increases of Arc protein, in
dendritic spines, are elicited by conventional paradigms of LTP induction.
110 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
BDNF and other factors. Interestingly enough, BDNF can
stimulate Arc synthesis in isolated synaptoneurosome
preparations (Yin et al., 2002).
6. 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, 2001; de Moor and Richter, 2001;
Johnstone and Lasko, 2001; Richter, 2001). As in these
systems, dendritic protein synthesis depends on coordinated
transport, localization, and translation of mRNA. All of
these mechanisms can be modulated by changes in synaptic
activity, suggesting an extraordinarily exquisite means for
controlling the time and place of protein synthesis (Wells
and Fallon, 2000; Steward and Schuman, 2003; Havik et al.,
2003; Klann and Dever, 2004). BDNF has emerged as one of
the major activity-dependent modulators of dendritic protein
synthesis.
While numerous (possibly hundreds) of mRNA species
have been localized to dendrites of cultured neurons, less
than twenty mRNAs have been identified in dendrites on
adult neurons (Steward, 1997).3 These mRNAs, exemplified
by aCAMKII, are considered to be stably expressed
(resident) in dendrites (Steward and Levy, 1982; Steward
et al., 1996; Steward, 1997). By contrast, Arc is only
transiently expressed in dendrites following its activity-
dependent induction.
In one of the first direct visualizations of dendritic protein
synthesis, BDNF induced hotspots of reporter GFP synthesis
in isolated dendrites from cultured hippocampal neurons
(Aakalu et al., 2001). In this study, dendritic localization of
the reporter was obtained by flanking the GFP sequence with
the 50 and 30 UTRs of aCaMKII. In adult CA3–CA1
synapses, BDNF-LTP can be obtained in slices in which the
CA1 dendrites and the CA3 axons are severed from the
respective cell bodies (e.g., the synaptic neuropil was
isolated) and this potentiation is abolished by protein
synthesis inhibitors (Kang et al., 1996). In the adult
hippocampus, immunocytochemical staining of CaMKII
protein is increased in CA1 pyramidal cell dendrites within
5 min of LTP induction (Ouyang et al., 1999), the speed of
this effect indicating local synthesis of CaMKII, rather than
transport from the cell body. BDNF also enhances synthesis
3 coworkers created a line of mice devoid of dendritic
It is still not clear whether this difference reflects a more selective
dendritic mRNA population in adult neurons or difficulties in detecting low
abundance mRNAs in adult neurons using in situ hybridization histochem-
istry (discussed in Job and Eberwine, 2001; Smith et al., 2001).
of CaMKII and Arc in synaptodendrosomes and synapto-
neurosomes, biochemical fractions enriched in excitatory
terminals attached to pinched-off resealed dendritic spines
preparations (Yin et al., 2002; Kelleher et al., 2004a;
Kanhema et al., 2003). Use of these synapto-dendritic
fractions effectively rules out protein transport and
facilitates pulse-chase labeling approaches. Together, these
studies indicate a role for local, BDNF-regulated protein
synthesis in synaptic plasticity. CaMKII and Arc are both
attractive mediators, but causal roles for the locally
synthesized proteins have not been established.
CaMKII protein is a major component of the PSD where
it plays a critical role in regulating the efficacy of
glutamatergic synapses. During the early phase LTP,
CaMKII activity enhances AMPA receptor conductance
and promotes the insertion of AMPA receptors into the
synaptic plasma membrane (Lisman et al., 2002, 2004;
Malinow and Malenka, 2002; Bredt and Nicoll, 2003). In
addition to these established enzymatic functions, CaMKII
probably also has structural functions as an integral
component of the PSD protein complex. CaMKII and other
resident dendritic mRNAs are thought to be stored in a
dormant state within RNA granules. Local protein synthesis
may therefore entail activity-dependent discharge of mRNA
from these storage granules (Krichevsky and Kosik, 2001;
Kosik and Krichevsky, 2002). Havik et al. (2003) examined
the expression of CaMKII mRNA and protein in synapto-
dendrosomes. Synaptodendrosomes were prepared from
homogenates of microdissected dentate gyrus collected at
different time points after LTP induction in awake rats. LTP
was associated with a rapid, transient increase in CaMKII
mRNA and protein in synaptodendrosomes, whereas no
changes were found in the whole homogenates. This study
suggested rapid delivery of stored, pre-existing aCaMKII
mRNA into the synaptodendritic compartment during LTP.
While the mechanisms are unknown it is interesting to note
that, like BDNF-LTP induction, the increase in CaMKII
mRNA did not require NMDA receptor activation. In a
quantitative ultrastructural study, Ostroff et al. (2002) used
3D reconstruction of serial sections to examine changes in
the distribution of polyribosomes in pyramidal cell dendrites
following LTP. LTP was associated with an increase in the
percentage of dendritic spines containing polyribosomes
commensurate with a decrease in shaft polyribosomes,
suggesting translocation of ribosomes into spines. Taken
together these studies suggest that mRNA and ribosomes are
transported into dendritic spines during LTP.
Miller et al. (2002) used a genetic approach to examine
the function of dendritically stored aCaMKII. Dendritic
targeting of aCaMKII mRNA depends on cis-acting
localization elements in the 30 untranslated region (UTR).
Removing the 30 UTR by targeted mutagenesis, Miller and
aCaMKII mRNA. Surprisingly, these mice had normal early
LTP and memory acquisition but impaired late LTP and
memory consolidation. This study was important in
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
Fig. 6. TrkB coupling to translation control pathways. This is a highly
simplified scheme depicting signaling pathways coupling activated TrkB
receptors to phosphorylation of eIF4E and eEF2. Phosphorylation of the
eIF4E is commonly associated with enhanced translation of capped
mRNAs. eIF4E is released from eIF4E binding protein and phosphorylated
by MNK. eEF2 promotes peptide chain elongation and phosphorylation of
EF2 arrests this activity. The spatial and temporal activation of these
pathways and the potentially important role of crosstalk have not been
resolved.
establishing a selective function for local CaMKII synthesis
in late LTP. However, the interpretation of these results was
complicated by the gross reduction in the size of the PSD in
the mutant mice. Thus, the key question of whether new
dendritic CaMKII synthesis contributes to LTP remains
unanswered.
Recent work has begun to explore the biochemical
mechanisms by which BDNF modulates local protein
synthesis (Fig. 6). The rate-limiting step in translation of
most mammalian mRNAs is phosphorylation of eukaryotic
initiation factor 4E (eIF-4E) (Gingras et al., 2004). eIF4E
binds to the 7-methyl-guanosine cap structure at the 50 end of
target mRNAs. Phosphorylation of eIF4E on Ser209 is
correlated with enhanced rates of translation, whereas
hypophosphorylation is associated with decreased transla-
tion (Flynn et al., 1997; Takei et al., 2001; Gingras et al.,
2004). eIF4E is phosphorylated by MAPK integrating kinase
(Mnk1), whose activity is regulated by ERK and p38
MAPK. The availability of eIF4E is controlled by binding
proteins (4E-BPs). Phosphorylation of 4E-BP releases
eIF4E and promotes cap-dependent translation (Gingras
et al., 2004). Trk-coupled PI3K is thought to stimulate
translation through activation of mammalian target of
rapamycin (mTOR or FRAP), a multifunctional serine/
threonine kinase that leads to phosphorylation of 4E-BPs
and ribosomal S6 kinase (Takei et al., 2004). Importantly,
the immunosuppressant drug rapamycin, which inhibits
mTOR, blocks both late LTP and BDNF-LTP at CA3–CA1
synapses (Cammalleri et al., 2003; Tang et al., 2002).
111
Several studies suggest a critical role for ERK signaling
in translation control underlying late LTP in the hippo-
campus. Using both dominant negative MEK mice and
pharmacological inhibitors of MEK activation, Kelleher
et al. (2004a) showed that eIF4E is phosphorylated through
an ERK signaling pathway in hippocampal neurons. In
MEK1 mutant mice, impaired eIF4E phosphorylation was
associated with specific deficits in translation-dependent late
LTP at CA3–CA1 synapses and impaired hippocampal-
dependent memory formation. In the dentate gyrus in vivo,
BDNF-LTP is coupled to an ERK-dependent phosphoryla-
tion of eIF4E (Kanhema et al., 2003). The synaptic actions
of BDNF were examined in vitro using synaptodendro-
somes. BDNF treatment of synaptodendrosomes led to rapid
(5 min) phosphorylation of eIF4E and enhanced expression
of aCaMKII, suggesting that BDNF triggers rapid, cap-
dependent translation of aCaMKII in the synaptodendritic
compartment. Finally, in addition to increasing eIF4E
phosphorylation, BDNF induces a redistribution of this
translation factor to an mRNA granule-rich cytoskeletal
fraction (Smart et al., 2003). Cap-independent initiation of
transcripts at internal ribosomal entry sites (IRESs) could
also be important, but these mechanisms have yet to
explored in the context of BDNF signaling and synaptic
plasticity (Dyer et al., 2003; Pinkstaff et al., 2001).
BDNF also regulates protein synthesis at the level of
peptide chain elongation (Fig. 6). Eukaryotic elongation
factor-2 (eEF2) is a GTP-binding protein that mediates
translocation of peptidyl-tRNAs from the A-site to the P-site
on the ribosome. Phosphorylation of eEF2 on Thr56 inhibits
ribosome binding and arrests mRNA transit along the
ribosome (Nairn and Palfrey, 1987; Ryazanov et al., 1988;
Nairn et al., 2001). In vivo BDNF-LTP is associated with a
transient ERK-dependent phosphorylation of eEF2 in whole
dentate gyrus (Kanhema et al., 2003). In contrast, net eEF2
phosphorylation is unchanged in BDNF-treated synapto-
dendrosomes. These data raise the possibility that BDNF has
compartmental (synaptic and non-synaptic) effects on eEF2
phosphorylation. Immunocytochemical localization of
phosphorylated translation factors is needed to resolve this
issue. Peptide chain elongation is energy-expensive and
metabolic states associated with reduced ATP levels are
typically associated with EF2 phosphorylation (Marin et al.,
1997; Browne and Proud, 2002; Chotiner et al., 2003).
Decreases as well as increases in protein synthesis are seen
during LTP (Fazeli et al., 1993; Chotiner et al., 2003).
Conceivably, inhibition of eEF2 serves to conserve
metabolic energy during periods of intensive protein
synthesis at synapses. Because the mRNAs are already
loaded onto ribosomes, protein synthesis is rapidly resumed
upon dephosphorylation of eEF2.
eIF4E and eEF2 affect the translation of a broad range of
mRNA species, and BDNF regulates the activity of both of
these translation factors during synaptic plasticity in the
dentate gyrus. In addition to these global controls, specific
alterations in neuronal function might depend on the
112 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
translation of smaller families of mRNA or even individual
mRNA species. Polyadenylation of the 30 UTR of target
transcripts represent one such mechanism of translation
activation. Polyadenylation induced activation of aCaMKII
translation has been demonstrated in the developing visual
cortex in vivo and in hippocampal neurons in vitro (Wu et al.,
1998; Wells et al., 2001; Huang et al., 2002). The
cytoplasmic polyadenylation binding protein (CPEB) binds
to recognition elements in the aCaMKII 30 UTR (Wells et al.,
2000; Huang and Richter, 2004). Phosphorylation of
threonine 171 on CPEB mediated either by Aurora kinase
or CaMKII results (in a sequence of steps not fully defined)
in polyadenylation-dependent enhanced translation (Atkins
et al., 2004). In addition, current evidence suggests that
eIF4E attaches to CPEB through the protein maskin, which
releases eIF4E upon CPEB phosphorylation.
Studies of long-term facilitation in Aplysia provide
perhaps the most compelling demonstration of local protein
synthesis-dependent synaptic plasticity (Casadio et al.,
1999; Sherff and Carew, 1999). Studying single, isolated
sensorimotor synapses, Casadio et al. (1999) showed that
local application of five puffs of serotonin induces synapse-
specific facilitation requiring local protein synthesis. In
Aplysia, local synthesis of CPEB protein is required for new
protein synthesis and maintenance of new synaptic
connections during long-term facilitation in sensory neurites
(Si et al., 2003a, 2003b; Bailey et al., 2004). The N-terminus
of the Aplysia CPEB protein has a prion-like switch which
may provide stable, self-perpetuating enhancement of
CPEB-regulated. In addition to this first characterized form
of CPEB, CPEB-1, three other members of the CPEB gene
family have been identified in mouse, CPEB-2–4 (Theis
et al., 2003). Mouse CPEB1 knockouts have only subtle
deficits in HFS-LTP and BDNF-LTP is normal (Alarcon
et al., 2004). The full story on BDNF and CPEB-dependent
protein synthesis awaits functional characterization of the
other mammalian isoforms.
Differential RNA display and microarray expression
profiling have identified several BDNF-regulated genes in
hippocampal cell cultures (Thakker-Varia et al., 2001; Alder
et al., 2003). BDNF treatment, which elicits only a transient
(10–15 min) increase in synaptic strength in immature
neurons, is associated with altered gene expression patterns
after 20 min and 3 h of BDNF exposure. Several immediate
early genes (arc, zif268, c-fos) were upregulated at both time
points. The transient increase in synaptic strength correlated
with enhanced Arc expression, as studied by single-cell PCR
analysis after whole-cell patch clamp (Alder et al., 2003).
One of the genes showing expression only at the late time
point is the secreted neuropeptide VGF. Application of VGF
protein enhanced synaptic strength during treatment in vitro,
and VGF mRNA expression was enhanced followed training
in eye-blink conditioning. In hippocampal cell cultures,
BDNF increases mTOR-dependent translation of a panel of
mRNAs that includes the synaptodendritically expressed
transcripts homer2 and GluR1 (Schratt et al., 2004). A recent
microarray-based screen in the adult brain identified five
novel BDNF-LTP regulated genes in the adult dentate gyrus,
all of which were validated by real-time PCR and in situ
hybridization (Wibrand et al., submitted for publication).
Further screens for regulated genes and loss-of-function
studies in the adult brain are needed.
In summary, regulation of synaptic strength through
dendritic synthesis will depend on availability of the
message for translation, the positioning of the translational
apparatus, and the biochemical regulation of translation
factors. BDNF is critically involved in all of these steps.
Glutamate is itself a major regulator of protein synthesis at
excitatory synapses (Weiler and Greenough, 1993; Kachar-
mina et al., 2000; Greenough et al., 2001; Ju et al., 2004;
Banko et al., 2004; Hou and Klann, 2004; Klann and Dever,
2004; Shin et al., 2004). It will be important to resolve how
BDNF and glutamate interact to regulate translation at
synaptic and non-synaptic sites.
7. Presynaptic mechanisms and retrograde nuclear
signaling
LTP involves coordinate pre- and postsynaptic modifica-
tions, 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 tran-
siently enhances presynaptic transmission (Lessmann and
Heumann, 1998; Jovanovic et al., 2000; Gooney and Lynch,
2001). Does BDNF also have an instructive presynaptic role
in LTP?
At perforant path-granule cell synapses, both quantal
analysis and biochemical studies support a contribution of
enhanced glutamate release to LTP expression (Errington
et al., 2003; Min et al., 1998). Evidence supporting a role for
BDNF in enhanced glutamate transmitter release during LTP
includes the following: (1) the maintenance phase of BDNF-
LTP, like HFS-LTP, is associated with a lasting increase in
potassium-evoked glutamate release from synaptosomes
(Gooney et al., 2004), (2) TrkB receptors are autopho-
sphorylated in synaptosomes collected during the main-
tenance phase of both HFS- and BDNF-induced LTP
(Gooney et al., 2002, 2004), (3) the Trk inhibitor, K252a,
blocks presynaptic Trk activation and the sustained
enhancement in neurotransmitter release. Finally, LTP
maintenance is associated with enhanced, depolarization-
evoked release of BDNF from dentate gyrus tissue (Gooney
and Lynch, 2001). There are two models for the presynaptic
actions of BDNF. BDNF released after HFS may induce a
persistent presynaptic modification resulting in enhanced
evoked neurotransmitter release. Alternatively, BDNF has
only transient presynaptic effects, but these are maintained
by a long-lasting secretion of BDNF. There is no data
discriminating between these scenarios at the moment.
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125 113

Fig. 7. BDNF hypothesis of synaptic consolidation. TrkB receptors are located pre- and postsynaptically at glutamate synapses. High-frequency afferent
stimulation (HFS) of synapse activates postsynaptic NMDARs leading to BDNF release. Postsynaptically, BDNF stimulates translation initiation in dendritic
spines, tagging these sites for capture of incoming mRNA. Putative mRNA species captured are Arc and aCaMKII. BDNF induces Arc mRNA which rapidly
trafficks along granule cell dendrites. aCaMKII released from local storage granules translocates into spines. Sustained synthesis of Arc during a critical time
window drives synaptic consolidation to completion. A regenerative loop of BDNF-induced BDNF release is proposed to be involved. On the presynaptic side
evidence suggests that BDNF signals retrogradely to activate CREB in the entorhinal cortex. See text for further explanation.

The classic hypothesis of target-derived trophic support
involves signaling from the nerve terminal to the nucleus.
Insights into the underlying molecular mechanisms have
come from studies of sympathetic and sensory neurons
(Riccio et al., 1997; Watson et al., 1999, 2001; Ginty and
Segal, 2002; Delcroix et al., 2003; Campenot and MacInnis,
2004). Neurotrophin binding to presynaptic Trk receptors
activates retrograde signaling pathways in axons leading to
activation of nuclear substrates, such as CREB, and
modulation of gene expression. The possible contribution
of retrograde nuclear signaling to LTP has not been explored
in any detail. However, recent evidence suggests that such
mechanisms may play a role. HFS of the perforant pathway
leads to CREB phosphorylation in the entorhinal cortex, and
this effect is blocked by intracerebroventricular application
of the Trk inhibitor K252a (Gooney and Lynch, 2001; Kelly
et al., 2000b). Similar effects are seen with BDNF-LTP
indicating that local signaling in the dentate gyrus leads to
retrograde activation of CREB in parent cell bodies located
some 4 mm away (Gooney et al., 2004).
8. 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 aCaMKII
mRNA (and presumably other mRNAs) and polyribosomes
from sites of storage in dendrites to sites of translation in or
near spines.4 Postsynaptic TrkB receptor activation leads to
ERK-dependent phosphorylation of eIF4E and local
enhancement of cap-dependent translation in dendritic
spines. ERK signaling to the nucleus activates CREB and
induces Arc gene expression.5 A fraction of Arc mRNA is
then trafficked to dendritic processes of granule cells. In this
model, translation activation coincides with the release of
mRNA from sites of local storage (mRNA granules) and the
arrival of newly synthesized Arc mRNA in dendrites. In this
way BDNF signaling may function to capture a local mRNA
pool, thereby restricting protein function to appropriate
synapses or dendritic domains. In the terminology of Frey
4
The mechanisms of aCaMKII redistribution is NMDAR-independent
(Havik et al., 2003).
5
Evidence that CREB regulates arc transcription is lacking. Using
primary hippocampal cultures and PC12 cells, Waltereit et al. (2001)
demonstrated ERK-dependent, cAMP- and calcium-inducible expression
of Arc. Unlike most CREB-responsive genes, no CRE consensus sequence
was found in the first 1737 bp of the Arc 50 regulatory region. It is possible
that the CRE sequence lies outside this region, as cells transfected with 50
(1737 bp) truncated Arc lose their responsivity to cAMP.
114 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
and Morris (1997), BDNF sets a synaptic tag (discussed in
Section 9).
The antisense studies suggest that Arc protein is rapidly
turned over and that continued synthesis of Arc during a
critical window is necessary for consolidation to occur. Once
consolidation is completed, Arc is degraded and plays no
role in the subsequent expression of the potentiated state.
This transient, yet critical, function of Arc indicates that it
mediates a coordinated cell biological process leading to
persistent changes in synaptic strength.
The cell biological function of Arc is unknown. Arc
localizes to the PSD, co-precipitates with F-actin, and
contains a spectrin homology repeats suggesting a structural
role (Lyford et al., 1995; Husi et al., 2000). Stable LTP is
associated with insertion of glutamate receptors at post-
synaptic membranes, thickening of the PSD, and increases
in spine size (Geinisman, 2000; Matsuzaki et al., 2004;
Weeks et al., 2001; Harris et al., 2003). Such changes are
intimately connected with regulation of actin dynamics
(Zhou et al., 2001; Fukazawa et al., 2003; Okamoto et al.,
2004; Zito et al., 2004). BDNF is implicated in insertion of
AMPA receptors and stabilization of AMPA receptors in the
membrane (Itami et al., 2003; Jourdi et al., 2003). Current
investigations in our laboratory are examining possible
contributions of Arc function to stabilization of the actin
network and synapse expansion.
The sites and dynamics of endogenous BDNF release and
TrkB activation in LTP remain to be elucidated in detail
(Lessmann et al., 2003). Storage and release of BDNF from
both presynaptic and postsynaptic elements have been
demonstrated, but major regional differences exist—no
general rules can be formulated at present (Androutsellis-
Theotokis et al., 1996; Fawcett et al., 1998; Balkowiec and
Katz, 2000, 2002; Kohara et al., 2001; Kojima et al., 2001;
Lever et al., 2001; Gartner and Staiger, 2002). In cultured
hippocampal neurons BDNF is released from postsynaptic
sites in response to HFS (Hartmann et al., 2001). In the
dentate gyrus, TrkB activation is enhanced 40 min after HFS
(Gooney and Lynch, 2001). Inhibition of TrkB signaling at
this time (at least in region CA1) inhibits late LTP formation
(Kang et al., 1997). It is possible that TrkB receptors
activated during LTP induction are maintained in a stably
phosphorylated state. However, the study of Kang and
coworkers using TrkB-Fc, which scavenges BDNF in the
extracellular space, underscores the importance of delayed
signaling by a diffusible TrkB ligand.
One possible mechanism for generating sustained BDNF
signaling is BDNF-induced BDNF release. Regenerative
autocrine loops of neurotrophin-induced neurotrophin
release have been implicated in the maintenance of sensory
neurons during development (Davies and Wright, 1995;
Kruttgen et al., 1998). BDNF has been shown to induce
BDNF release through TrkB-coupled PLC activation and
mobilization of intracellular calcium in hippocampal
neurons (Canossa et al., 1997, 2001). Mizoguchi and
Nabekura (2003) have reported long-lasting (90 min)
increases in neuronal intracellular calcium concentration
following a 3 min BDNF perfusion of visual cortex slices.
Even puff application of BDNF to apical dendrites of
hippocampal pyramidal cells elevates calcium for 1–2 min
(Amaral and Pozzo-Miller, 2005). Interestingly, BDNF-
induced mobilization of intracellular calcium is amplified
by calcium entry from the extracellular space, possibly
through the plasma membrane non-selective cationic
channel, TRPC (transient receptor potential C) (Li et al.,
1999; Amaral and Pozzo-Miller, 2005). Recent work
suggests that coupling of TRPC family channels to IP3
receptors may be regulated by another LTP-regulated
immediate early gene, homer1a (Yuan et al., 2003). Finally,
potassium-evoked release of endogenous BDNF is
enhanced in dentate gyrus tissue slices collected following
in vivo induction of HFS-LTP (Gooney and Lynch, 2001)
and BDNF-LTP (unpublished observation). Regenerative
BDNF signaling at glutamate synapses may provide an
effective means of driving synaptic consolidation (i.e.,
postsynaptic translation and presynaptic retrograde signal-
ing) in an activity-dependent manner.
As emphasized before, BDNF signaling is involved in
both the induction and consolidation of LTP. How is it that
BDNF modulates both steps, and are these events coupled in
any way? A recent study performed in organotypic
perirhinal cortex slices provides an important clue (Aicardi
et al., 2004). Measuring BDNF levels in perfusate samples,
these authors showed that stimulation patterns generating
late phase LTP trigger relatively persistent (5–12 min)
increases in BDNF secretion, whereas stimulation producing
only early LTP leads to smaller and shorter lasting (<1 min)
increases in secretion. This suggests that short-lasting
BDNF release, while capable of modulating early LTP, is
insufficient for generating late LTP. The finding also
dissociates the mechanisms involved in acute and more
sustained BDNF release. Numerous questions remain. Is
BDNF release actually enhanced at synaptic sites? (More
direct imaging approaches are needed to address this issue.)
If a BDNF signaling loop exists, how is it initiated and
terminated? Does sustained release involve re-exocytosis of
endocytosed BDNF or release from previously loaded
secretory granules?
Recent work in region CA1 provides compelling
evidence for release of pro-BDNF during LTP (Pang
et al., 2004). The pro-BDNF peptide is cleaved by
extracellular proteases (tissue plasminogen activator/plas-
min) to generate mature BDNF, which activates TrkB.
Future studies must also consider the role of p75NTR, which
is preferentially activated by pro-BDNF (although a study
using blocking antibodies to p75NTR reported no effect on
LTP (Xu et al., 2000)).
Our knowledge of the signal transduction pathways and
molecular effectors governing BDNF-regulated plasticity is
based almost exclusively on the effects of exogenously
applied BDNF. More studies involving blockade of
endogenous BDNF-TrkB are needed to determine the range
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
of critical signaling events underlying synaptic consolida-
tion. For example, although exogenous BDNF does not
induce zif268 gene expression in adult dentate gyrus,
endogenous TrkB coupling to ERK-CREB may be critical
for this activation (Ying et al., 2002), either by interacting
with a convergent transcription factor pathway or by
promoting nuclear translocation of ERK (Patterson et al.,
2001; Rosenblum et al., 2002).6
There are also important outstanding issues regarding the
contributions of TrkB-coupled PLC and Shc signaling to
late LTP (Minichiello et al., 2002; Ernfors and Bramham,
2003; Koponen et al., 2004b). To address this issue knock-in
mice were created in which the tyrosine docking site for
either PLCg or Shc was mutated to phenylalanine. Only the
TrkB-PLC site mutants exhibited deficits in late LTP at
CA3–CA1 synapses. Biochemical analyses of these mice
showed that TrkB-PLCg signaling was coupled to activa-
tion of nuclear CaMKIV and CREB activation. This elegant
work strongly suggested that TrkB-PLC, but not TrkB-Shc-
ERK, signaling is necessary for LTP. The results are
surprising given the requirement for ERK signaling in late
LTP, BDNF-LTP, and other BDNF-regulated transcriptional
responses. While the LTP work was performed on CA3–
CA1 synapses of adult hippocampal slices, the biochemical
signaling was assessed in immature dissociated neurons.
One must ask what happens to the PLC and Shc-ERK
signaling pathways during LTP induction. A growing body
of evidence suggests an increase in the diversity and
subcellular specificity of TrkB-coupled signaling pathways
with maturation of the nervous system (Qian et al., 1998;
York et al., 2000; Patapoutian and Reichardt, 2001). The
repertoire of TrkB responses may be expanded by the
formation of additional tyrosine docking motifs (including
binding sites for one or more Shc family proteins), as well as
subcellular compartmentalization (and thus restricted
availability) of the adaptor proteins. In addition, the
appropriate ERK response in adult neurons may be a
consequence of cross-talk between the TrkB-ERK and PLC
coupled pathways. For instance, TrkB activation can trigger
nuclear translocation of ERK without increasing ERK
activity (Patterson et al., 2001).
9. 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
6
The zif268 promoter contains five (mouse) serum-response elements
(SREs) and only one CRE-like element. In several systems involving ERK-
dependent regulation, the zif268 gene is under dominant control by SREs
(McMahon and Monroe, 1995; Davis et al., 2000; de Jager et al., 2001;
Gineitis and Treisman, 2001).
115
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 stable LTP on the weak
input was insensitive to protein synthesis inhibition. This
suggests that weak stimulation leads to a hijacking of
proteins (or secondary effects of these proteins) produced
following strong stimulation on input 1.
How does BDNF fit into current thinking on synaptic
tagging (Martin and Kosik, 2002)? One possibility is that
BDNF enhances regional protein synthesis thereby gen-
erating a local pool of proteins for capture by tagged
synapses. Another distinct possibility is presented in the
synaptic consolidation hypothesis—that BDNF sets a
synaptic tag, but for capture of mRNA rather than protein.
In the synaptic consolidation hypothesis synapses are tagged
through TrkB-dependent phosphorylation of eIF4E leading
to enhanced translation rates. Such a mechanism may serve
to facilitate translation (and thus capture) of mRNA
liberated from local storage granules (aCaMKII) as well
as newly induced RNA (such as Arc) traveling along
dendrites. The difficulty is that expression of this tag in
response to input 2 would require protein synthesis, putting
it at odds with the data of Frey and Morris. It should be
emphasized, however, that the tagging phenomenon has
been thoroughly studied only in the CA1 region, whereas
evidence for Arc-dependent consolidation has only been
obtained in the dentate gyrus. Regional differences in the
kinetics of the tag may exist. Striking differences between
brain regions in the kinetics of activity-induced Arc mRNA
expression have been reported (Kelly and Deadwyler, 2003).
Recent work shows a more rapid decline in Arc protein
levels in the CA1 region compared to the dentate gyrus
following spatial exploration (Ramirez-Amaya et al., 2004).
Similarly, only short-lived increases in Arc mRNA are seen
in CA1 pyramidal cells following LTP induction. Thus, Arc-
dependent consolidation in CA1, if it exists, is likely to be of
much shorter duration than in the dentate gyrus. In this case,
a protein synthesis-dependent expression of the tag would
not be expected in the paradigm used by Frey and Morris.
Work on long-term facilitation in Aplysia sensory neurons
has already suggested the existence of protein synthesis-
dependent and independent tags occurring at different time
points in the same cell (Martin et al., 1997; Casadio et al.,
1999; Martin and Kosik, 2002).
10. 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 Tables 1–3). 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
116 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
induced by cluster tetanus.7 Second, late phase LTP induced
by spaced tetanus protocols is blocked by pharmacological
inhibitors of BDNF/TrkB, while early phase LTP is not.
While there are still no cut and dry answers, current
evidence suggests that these differences reflect the amount,
duration, and possibly even the subcellular site of BDNF
release. The study of Zakharenko et al. (2003) indicates that
TBS-LTP is expressed presynaptically and requires pre-
synaptic release of BDNF. TBS-LTP may be more sensitive
to pharmacological inhibitors because it is more effective
than cluster tetanus (i.e., 100 Hz 1 s) in releasing BDNF
(Balkowiec and Katz, 2002). Modulation of LTP and LTD by
co-stored neuropeptides (enkephalins and dynorphins)
released in a frequency-dependent manner has been shown
in several excitatory hippocampal pathways (Bramham,
1992; Wagner et al., 1993; Weisskopf et al., 1993; Breindl
et al., 1994; Derrick and Martinez, 1994; Bramham and
Sarvey, 1996). Like neuropeptides stored in large dense-core
vesicles, exocytosis of BDNF-containing secretory granules
is a relatively slow process (on the order of seconds).8 TBS
stimulation typically lasts several seconds, which is long
enough to allow BDNF release and modulation of LTP
induction. In addition, Aicardi et al. (2004) found that
spaced stimulation that induces late phase LTP also evokes
much larger and longer-lasting increases in BDNF release. It
is possible that the buffering capacity of the inhibitors is
saturated by the large amounts of BDNF released by spaced
stimulation paradigms. Another facet of this issue is that all
of the inhibitors used to date are relatively bulky antibodies
that may not effectively penetrate the synaptic cleft to block
TrkB activation. When genetic approaches are used both
early and late LTP is inhibited.
11. 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 mm)
effects on dendritic outgrowth, suggesting very limited
diffusion (Horch and Katz, 2002). Truncated TrkB may
serve to concentrate BDNF to sites of release. By the same
token, truncated TrkB may curtail access of exogenously
applied BDNF to full-length TrkB receptors within
excitatory synapses. Several authors have failed to observe
7
Cluster = multiple sessions of stimulation separated by 30 s or less.
Spaced = multiple sessions of stimulation separated by at least 5 min.
8
Postsynaptically, BDNF is released from secretogranin II positive
secretory vesicles (Lessmann et al., 2003). Presynaptically, at least in dorsal
root ganglion neurons, BDNF is released from large dense core vesicles
(Luo et al., 2001).
BDNF-LTP in hippocampal slices (Figurov et al., 1996;
Patterson et al., 1996; Scharfman, 1997; Frerking et al.,
1998). Consistent with the notion of a diffusion barrier,
BDNF-LTP in the hippocampal slice preparation has been
observed only with use of high rates of bath application,
correlating with increased penetration of BDNF into the
slice (Kang et al., 1996). Recent work employing high
perfusion rates have demonstrated BDNF-LTP at CA3–CA1
synapses (Alarcon et al., 2004), providing an important
replication of the original studies of Schuman and
coworkers. In the in vivo studies BDNF is applied as a
concentrated bolus, which may be a more effective means of
saturating the diffusion barrier. The developmental upregu-
lation of truncated TrkB may therefore explain some of the
discrepancies in the literature with regard to the effects of
BDNF application (Table 3).
12. 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 rapidly enhancing
acetylcholine release (Oosawa et al., 1999; Auld et al.,
2001). Contextual fear conditioning is associated with
enhanced NGF protein expression, while antisense knock-
down of TrkA expression in the medial septum impairs
memory consolidation and reduces the cholinergic cell body
size and the expression of markers in cholinergic terminals
(Woolf et al., 2001). The case for NGF involvement in LTP is
more circumstantial. TrkA receptors are activated following
LTP and NGF mRNA expression is enhanced (Bramham
et al., 1996; Kelly et al., 2000a). NGF, like BDNF, increases
glutamate release from synaptosomes. However, exogen-
ously applied NGF has no lasting effect on synaptic
transmission (Kang and Schuman, 1995). Incubation of
slices with anti-p75NTR antibody does not affect synaptic
responding during HFS nor does it impair CA3–CA1 LTP
(Xu et al., 2000). There have been no reports on the effects of
selective NGF or TrkA receptor blockade.
NT-3 is strongly expressed in granule cells and CA2
pyramidal cells but only weakly expressed in fields CA3 and
CA1. In the only study examining endogenous NT-3
function in LTP, conditional NT-3 deletion was obtained
using the synapsin 1 promoter to drive expression of Cre
recombinase (Ma et al., 1999). NT-3 deletion had no effect
on LTP induced by 100 Hz stimulation or TBS in the CA1
region. NT-3 antibodies similarly are without effect on LTP
induced by these paradigms (Chen et al., 1999). NT-3
mRNA expression is also increased after LTP (Patterson
 C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125
et al., 1992). In the dentate gyrus of freely moving rats,
NMDAR-dependent LTP is associated with a rapid increase
TrkC mRNA expression followed by a delayed increase in
NT-3 expression (Bramham et al., 1996). The significance of
this sequential pattern of expression is unclear. NT-3, like
BDNF, induces a slowly developing potentiation that is
protein synthesis-dependent and requires mobilization of
intracellular calcium (Kang and Schuman, 1995, 1996,
2000). As pointed out by Ma et al. (1999), the effect of
exogenous NT-3 may be mediated by TrkB receptors that are
activated by high concentrations of NT-3. Studies comparing
the lateral and medial perforant path inputs to dentate
granule cells have revealed a remarkable specificity in the
effects of BDNF and NT-3 (Kokaia et al., 1998; Asztely
et al., 2000; Olofsdotter et al., 2000). Paired-pulse plasticity
is altered in the lateral, but not in the medial, pathway in
slices from heterozygote NT-3 knockout mice. Conversely,
paired-pulse plasticity in the medial, but not lateral,
perforant path, is altered in BDNF+/
mice or following
incubation with TrkB-Fc. Although synaptic fatigue is
increased in the lateral perforant path of NT-3+/
mice, LTP
in response to 100 Hz tetanus is not affected.
There has been one study on NT-4 function in LTP (Xie
et al., 2000). NT-4 knockouts are impaired in LTP induced
by spaced tetanus (4  100 Hz), but not single tetanus. This
suggests that NT-4 activation of TrkB may contribute to late
phase LTP in region CA1.
13. 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: permissive, acute instructive, and
delayed instructive. This is valuable because it means that
perturbations in BDNF function in disease states, which
could affect one or more of these mechanisms, might be
specifically targeted therapeutically. Yet even as the
molecular targets are separated and defined, we must not
lose sight of the broader picture of BDNF function. How do
the different functions of BDNF overlap and interact in
behaving animals? For instance, how will changes in
permissive BDNF signaling affect instructive mechanisms
in LTP, target-derived trophic support, and neurogenesis?
In the dentate gyrus, BDNF appears to drive synaptic
consolidation through dual effects on postsynaptic gene
expression (Arc) and local protein synthesis. A major goal is
to delineate the cell biological function of Arc in the
consolidation process. A better understanding of Arc
regulation could lead to very specific ways of contracting
117
or expanding the window of synaptic consolidation with
potential implications for the management of memory
disorders and unipolar depression. Paralleling studies of
synaptic plasticity, there is growing evidence that BDNF-
TrkB contributes to acquisition and long-term memory
formation in a variety of learning tasks (Linnarsson et al.,
1997; Minichiello et al., 1999; Hall et al., 2000; Mizuno
et al., 2000; Alonso et al., 2002; Gooney et al., 2002; Tyler
et al., 2002a; Lee et al., 2004; Koponen et al., 2004a, 2004b).
BDNF is also increasingly implicated in the pathogenesis of
depression and the action of antidepressant drugs (Nestler
et al., 2002; Monteggia et al., 2004). While BDNF infusion
induces Arc-dependent synaptic strengthening in the dentate
gyrus (Messaoudi et al., 2005; Ying et al., 2002), a nearly
identical bilateral infusion of BDNF has antidepressant-like
effects in behaving rats (Shirayama et al., 2002).
With regard to BDNF control of synaptic consolidation it
will be important to determine the relationship between Arc,
zif268 and other LTP-regulated genes. Arc synthesis would
be expected to precede, yet overlap with, transport of late
gene products from the cell soma. There is no reason to
suspect that Arc is acting alone. In addition to zif268 and
other IEGs, the list of critical players includes a
constitutively active form of a protein kinase C isozyme,
PKM-zeta, N-cadherin, and members of the integrin
receptor family (Bahr et al., 1997; Bozdagi et al., 2000;
Ling et al., 2002; Chan et al., 2003). Elucidating this mosaic
of molecular interactions and its functional regulation in
living animals represents one of the greatest challenges for
the future.
Acknowledgements
Funded by the European Union Biotechnology program
(BIO4-CT98-0333) and the Norwegian Research Council.
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