bdnf function in adult synaptic plasticity_the synaptic consolidation hypotesis

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

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Progress in Neurobiology 76 (2005) 99–125

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: [email protected] (C.R. Bramham).

0301-0082/$ – see front matter # 2005 Elsevier Ltd. All rights reserved.

doi:10.1016/j.pneurobio.2005.06.003

C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005) 99–125100

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

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

integrated understanding of BDNF function in synaptic

plasticity is lacking. The role of BDNF in visual cortical

plasticity is covered in several recent papers and will not be

discussed here (Akaneya et al., 1996, 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) 99–125 101

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

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


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.


Table 1

Effect of genetic manipulations of BDNF/TrkB on LTP

Genetic manipulation Stimulation parameters Fatigue Induction E-LTP L-LTP References

BDNF ko +/� and �/� 2 � Tet, cluster ND # # n.a.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

reduction (fBZ/fBZ)

2 � Tet cluster " # # ND Xu et al. (2000)

Pairingc n.a. – – ND

trkB-cre CA1-KO 2 � Tet cluster " #d # ND

trkB-cre heterozygouse 3 � TBS cluster – – # ND Minichiello et al.

(1999, 2002)trkB-cre homozygous 3 � TBS cluster – # ##f #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.


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

15 min post-HFS

3 � Tet spaced ND – – # Kang et al. (1997)

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

of recordingb

3 � TBS cluster n.a. n.a. – –

Photoactivation of Ab 2 min pre-HFS

to 2 min post-HFS

3 � TBS cluster ND # # for �30 min ND Kossel et al. (2001)

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

Table 3

Effect of exogenous BDNF application on excitatory synaptic transmission in th

Preparation Application method Effect on EPSPs

Primary hippocampal

cultures

Incubation Transient increase

(�20 min duration)

Acute hippocampal

slicea

Bath perfusion

CA3–CA1 synapse

None

None

Long-lasting increase

Bath incubation None

Brief (1 s) puff from

micropipette

No lasting effect

In vivo anesthetized

dentate gyrus

Brief (25 min)

local infusion

Long-lasting increase

a CA3–CA1 synapses studied.

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

e hippocampus

Other effects/comments References

Lessmann et al. (1994)

Levine et al. (1995b)

Li et al. (1998)

Impairs synaptic fatigue & enhances

LTP induction in P12–13 rats

Figurov et al. (1996)

Small # evoked IPSCs.

High perfusion rates used

Frerking et al. (1998)

High perfusion rates required Kang and Schuman (1995)

Kang et al. (1996)

Alarcon et al. (2004)

Patterson et al. (1996)

Induces rapid depolarization.

Pairing with current injection gives LTP

Kafitz et al. (1999)

Kovalchuk et al. (2002)

Messaoudi et al. (1998)

Messaoudi et al. (2002)

Ying et al. (2002)


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.

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.


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


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

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-


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

Fig. 4. BDNF-LTP induction, but not maintenance, requires ERK signaling. (a)

fEPSPs. Infusion of the MEK inhibitor U0126 (30 mM) into the dentate gyrus imme

BDNF-LTP induction. Control BDNF infusion (open bar). (b) The same applicatio

activation is seen in the dentate gyrus (DG) but not in the CA1 and CA3 regi

immunoreactivity in homogenates of BDNF-treated DG relative to contralateral co

from Ying et al. (2002).

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,

BDNF infusion (open bar) induces LTP of medial perforant path-evoked

diately before (black bar) and during BDNF infusion (hatched bar) abolished

n of MEK inhibitor 2 h after BDNF infusion had no effect. (c) Rapid ERK

ons of the hippocampus. The bar graph shows changes in phospho-ERK

ntrol. U0126 blocked ERK activation in parallel with BDNF-LTP. Adapted


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).

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.


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 30UTRs 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 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 30UTR by targeted mutagenesis, Miller and

coworkers created a line of mice devoid of dendritic

aCaMKII mRNA. Surprisingly, these mice had normal early

LTP and memory acquisition but impaired late LTP and

memory consolidation. This study was important in


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).

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


translation of smaller families of mRNA or even individual

mRNA species. Polyadenylation of the 30UTR 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 30UTR (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.


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.

4 The mechanisms of aCaMKII redistribution is NMDAR-independent

(Havik et al., 2003).

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).
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.

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


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


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 CaMKIVand 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).

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


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


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

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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