neurotrophins and synaptic plasticity · p1: kkk/vks/ary p2: ars/vks qc: ars december 10, 1998 14:8...

P1: KKK/VKS/ARY P2: ARS/vks QC: ARS

December 10, 1998 14:8 Annual Reviews AR076-13

Annu. Rev. Neurosci. 1999. 22:295–318Copyright c© 1999 by Annual Reviews. All rights reserved

NEUROTROPHINS ANDSYNAPTIC PLASTICITY

A. Kimberley McAllisterHoward Hughes Medical Institute, Molecular Neurobiology Laboratory, Salk Institute,La Jolla, California 92037; e-mail: [email protected]

Lawrence C. Katz1, 2 and Donald C. Lo21Howard Hughes Medical Institute,2Department of Neurobiology, Duke UniversityMedical Center, Durham, North Carolina 27710; e-mail: [email protected],[email protected]

KEY WORDS: BDNF, Trk, LTP, synaptogenesis, synaptic transmission

ABSTRACT

Despite considerable evidence that neuronal activity influences the organizationand function of circuits in the developing and adult brain, the molecular signalsthat translate activity into structural and functional changes in connections remainlargely obscure. This review discusses the evidence implicating neurotrophins asmolecular mediators of synaptic and morphological plasticity. Neurotrophins areattractive candidates for these roles because they and their receptors are expressedin areas of the brain that undergo plasticity, activity can regulate their levels andsecretion, and they regulate both synaptic transmission and neuronal growth.Although numerous experiments show demonstrable effects of neurotrophins onsynaptic plasticity, the rules and mechanisms by which they exert their effectsremain intriguingly elusive.

INTRODUCTION

Particular spatial and temporal patterns of electrical activity, such as coincidentactivity in the pre- and postsynaptic neurons of a synapse (Hebb 1949), arewidely believed to regulate the efficacy of synaptic transmission. Such use-dependent forms of synaptic plasticity encompass a wide range of structuraland functional modifications covering timescales ranging from milliseconds toyears. During development, patterns and levels of activity are believed to form

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296 MCALLISTER, KATZ & LO

the basis of competition between different axons for postsynaptic targets bystabilizing and elaborating coincident inputs and weakening and removing non-coincident inputs (reviewed by Goodman & Shatz 1993, Katz & Shatz 1996).In the adult, particular patterns of coincident activity in presynaptic inputs andpostsynaptic cells induce both short- and long-term synaptic changes, provid-ing potential mechanisms for learning and memory (reviewed by Madison et al1991, O’Dell et al 1991, Bailey & Kandel 1993, Hawkins et al 1993, Stevens1993, Malinow 1994, Bear & Malenka 1994, Larkman & Jack 1995). A diverseset of molecular signals is presumably involved in translating these differentpatterns of activity into changes in synaptic connectivity and efficacy, but theidentity of most such signals in the mammalian brain has remained obscure,especially on the longer timescale of days to years.

Recently, the neurotrophins have emerged as attractive candidates for suchsignaling molecules and have been proposed to play central roles in a variety offorms of synaptic plasticity (reviewed by Fox & Zahs 1994, Lo 1995, Thoenen1995, Bonhoeffer 1996, Snider & Lichtman 1996). The neurotrophins com-prise a family of at least four structurally related proteins—nerve growth factor(NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), andneurotrophin-4/neurotrophin-5 (NT-4/5)—that exert their effects through twoclasses of receptors, high-affinity tyrosine kinase receptors (Trk receptors) anda lower-affinity receptor, p75 (for reviews, see Bothwell 1991, Chao 1992,Meakin & Shooter 1992, Barbacid 1994, Dechant et al 1994, Lindsay et al1994, Ip & Yancopolous 1996, Segal & Greenberg 1996). NGF, the prototypi-cal member of this family, has been clearly defined as a target-derived trophicfactor required for the survival of certain types of peripheral neurons; by exten-sion, the other neurotrophins are thought to play similar roles for other neuronalpopulations, especially in the peripheral nervous system (PNS) (reviewed byLevi-Montalcini 1987, Purves 1988, Barde 1989, Oppenheim 1991, Davies1994, Snider 1994, Bothwell 1995, Lewin & Barde 1996).

This review will focus on evaluating evidence that neurotrophins, beyondtheir role as permissive survival factors, also mediate important forms of synap-tic plasticity, particularly in the central nervous system (CNS). For compre-hensive reviews of cellular mechanisms of synaptic plasticity, neurotrophinsignal transduction, and other biological actions of neurotrophins, the readeris referred to numerous substantial reviews that have been published recently(e.g. Barde 1989, Madison et al 1991, Chao 1992, Meakin & Shooter 1992,Korsching 1993, Stevens 1993, Barbacid 1994, Bear & Malenka 1994, Heumann1994, Malinow 1994, Bothwell 1995, Larkman & Jack 1995, Ip & Yancopolous1996, Lewin & Barde 1996, Segal & Greenberg 1996).

In order to play a meaningful role in synaptic plasticity, the neurotrophinsmust satisfy the following criteria:

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NEUROTROPHINS AND PLASTICITY 297

1. Neurotrophins and their cognate receptors must be expressed in the rightplaces and at the right times for the form of synaptic plasticity being con-sidered.

2. Neurotrophin expression and secretion must be activity dependent.

3. Neurotrophins must regulate aspects of neuronal function that change ac-tivity in neural circuits, including synaptic function, membrane excitability,and neuronal morphology and connectivity.

The following sections will consider each of these requirements in turn.

NEUROTROPHINS AND THEIR RECEPTORS AREPRESENT IN THE CENTRAL NERVOUS SYSTEMDURING PERIODS OF SYNAPTIC PLASTICITY

The first requirement for neurotrophins as molecular mediators of synapticplasticity is that they be present in the relevant locations in the CNS duringtimes of developmental or adult plasticity.

Distribution of Neurotrophins and Their ReceptorsThe expression of the neurotrophins and their receptors has been studied pri-marily at the mRNA level by in situ hybridization. BDNF, NT-3, and NT-4/5and their receptors, TrkB and TrkC, are widely and specifically distributed inthe CNS, whereas NGF expression is restricted to defined areas of the CNSsuch as striatal and basal forebrain cholinergic neurons (reviewed by Chao1992, Barbacid 1994, Lindsay et al 1994). BDNF and NT-3 and their cognatereceptors, TrkB and TrkC, are particularly highly expressed in the cerebellum,hippocampus, and cerebral cortex, all well-studied sites of both developmentaland adult synaptic plasticity. In situ hybridization studies further indicate thatfull-length, kinase-containing forms of TrkB and TrkC are expressed, and oftencoexpressed, on most CNS neurons but not on nonneuronal cells. In contrast,truncated, noncatalytic forms of both TrkB and TrkC are found in both neuronsand glial cells (reviewed by Barbacid 1994, Lindsay et al 1994).

In addition to their specific patterns of expression in the adult CNS, theneurotrophins and their receptors are developmentally regulated (reviewed byDavies 1994). BDNF, NT-3, and NT-4/5 mRNA levels increase in abundancewith postnatal age (Maisonpierre et al 1990, Friedman et al 1991, Timmusk et al1993a), and in rats, mRNA levels for TrkB and TrkC transiently peak betweenpostnatal day 1 (P1) and P14 in several different brain regions, correlating withmaximal neuronal growth, differentiation, and synaptogenesis (Ernfors et al1990, Dugich-Djordjevic et al 1992, Ringstedt et al 1993, Altar et al 1994,

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Knusel et al 1994). In the developing ferret visual system TrkB immunoreac-tivity increases specifically in separate locations at times of neuronal growthand synaptogenesis (Cabelli et al 1996).

Although this specific spatial and temporal distribution of the neurotrophinand Trk receptors indicates that they are likely to be in the right place at theright time to be involved in both developmental and adult plasticity, many basicquestions about their expression remain unanswered. First, there may not be apredictable relationship between mRNA and protein levels of neurotrophins; infact, BDNF mRNA and protein have been shown to be regulated independentlyfollowing seizure activity in the hippocampus (Wetmore et al 1994) and duringvisual system development in chickens (Johnson et al 1997).

mRNA expression studies have been further complicated by the existenceof multiple isoforms of each of the principal Trk receptors. For example, atleast seven distincttrkB transcripts encoding both full-length and truncatedTrkB receptors (Klein et al 1990a,b; Middlemas et al 1991) and multipletrkCtranscripts, encoding at least three distinct kinase domain variants and truncatedforms of TrkC (Valenzuela et al 1993, Tsoulfas et al 1993), have been identifiedin the CNS. Studies using antibodies to detect protein levels directly have alsobeen problematic, especially for Trk receptors, since antibodies reliably specificfor each Trk receptor isoform are just now becoming available.

Most methods available for neurotrophin localization to date also suffer froma lack of sufficient sensitivity. Neurotrophins are likely to be secreted in verysmall amounts, and only a few Trk receptors may be required for neurotrophinfunction, perhaps both beyond the level of detection with current technology.Such technical difficulties have particularly hampered progress in studying thesubcellular localization of endogenous neurotrophins and their receptors, oneof the most pressing issues in the field.

REGULATION OF NEUROTROPHINS BY ACTIVITY

Effects of Activity on Neurotrophin ExpressionRegulation of neurotrophin mRNA expression by electrical and synaptic ac-tivity was first demonstrated in the hippocampus, where high basal levels ofneurotrophins are present. NGF and BDNF mRNA levels are rapidly and po-tently upregulated by epileptiform activity in the hippocampus and cerebralcortex (Gall & Isackson 1989, Zafra et al 1990, Ernfors et al 1991, Isacksonet al 1991, Dugich-Djordjevic et al 1992). Similarly, neuromuscular activitystrongly regulates NT-4/5 mRNA levels in skeletal muscle (Funakoshi et al1995). In the hippocampus, changes in BDNF mRNA levels are particularlydramatic, increasing by over sixfold in dentate granule cells within 30 min af-ter seizure induction (Ernfors et al 1991). Interestingly, similar manipulations

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reduce NT-3 expression (Castren et al 1993, Elmer et al 1996, Mudo et al1996).

Manipulations meant to mimic neuronal activity are particularly effective inregulating neurotrophin mRNA levels in dissociated neuronal cultures. Depo-larization of cultured hippocampal neurons and cerebellar granule cells withglutamate receptor agonists or high potassium, for example, dramatically in-creases the levels of mRNAs encoding BDNF and NGF (Lu et al 1991; Zafraet al 1990, 1991, 1992; Berzaghi et al 1993; Berninger et al 1995; Bessho et al1993; Lindholm et al 1994). Conversely, BDNF and NGF levels are down-regulated in the presence ofγ -aminobutyric acid (GABA) through activationof GABAA receptors (Zafra et al 1991, 1992; Berzaghi et al 1993; Berningeret al 1995). These treatments cause rapid changes in neurotrophin mRNA lev-els; for example, BDNF mRNA levels increase by greater than 10-fold within3 h after stimulation with the non-NMDA receptor agonist, kainate (Zafra et al1991). This activity-dependence of BDNF expression involves only a subsetof the multiple promoters that direct BDNF transcription and is dependent oncalcium entry and the activation of the transcription factor CREB (Timmusket al 1993b, 1995; Shieh et al 1998; Tao et al 1998).

There are at least two major limitations to the studies described above.First, the relationship between changes in neurotrophin mRNA levels and ac-tual changes in protein levels needs to be investigated; indeed, BDNF mRNAand protein levels are known to be regulated differently after kainate-inducedseizures in the hippocampus (Wetmore et al 1994). Thus, direct protein mea-surements in such experiments will be important. Second, most studies onactivity-mediated neurotrophin regulation have used stimuli whose relation-ship to naturally occurring levels and patterns of synaptic activity are unknown.For example, there are major differences between the effects induced by depo-larization or total elimination of “activity” (such as adding KC1 to a culture, orblocking all activity with tetrodotoxin) and those elicited by more physiologicalforms of activity, which revolve around circuitry-driven changes in the numberand/or pattern of action potentials and synaptic events.

In this context, it is important that more physiological levels of activity havealso been shown to strongly regulate neurotrophin mRNA levels. Induction ofhippocampal long-term potentiation (LTP), for example, rapidly and selectivelyincreases BDNF mRNA levels, with little or no effect on the other neurotrophins(Patterson et al 1992, Castren et al 1993, Dragunow et al 1993); similar increasesin BDNF mRNA levels are seen after induction of long-term depression (LTD)in the cerebellum (Yuzaki et al 1994). Large changes in the levels of physio-logical stimuli, such as light, also regulate the production of BDNF and TrkBin the visual system (Castren et al 1992, Schoups et al 1995, Bozzi et al 1995,Rocamora et al 1996). In future experiments, it will be desirable to use even

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more subtle and regional manipulations resembling those of natural patterns ofneuronal activity to determine the full range of physiological relevance of suchactivity dependence.

Effects of Activity on Neurotrophin SecretionAlthough neurotrophin secretion in the PNS is generally constitutive (Barthet al 1984), recent evidence suggests that central neurons and muscle cells mayrelease neurotrophins through activity-regulated release pathways (Blochl &Thoenen 1995, Wang & Poo 1997). Secretion of NGF from hippocampal slicesand dissociated hippocampal neurons overexpressing NGF is increased by highpotassium depolarization, glutamate, and acetylcholine (Blochl & Thoenen1995, 1996). Similarly, BDNF secretion from BDNF-overexpressing dissoci-ated hippocampal neurons is increased fivefold by depolarization (Goodmanet al 1996). Consistent with this suggestive evidence, endogenous BDNF in hip-pocampal neuron dendrites has been localized to dense-core vesicles, whichare potentially capable of undergoing regulated release (Fawcett et al 1997,Smith et al 1997, Moller et al 1998). Activity-dependent secretion of NT-4/5from transfected myocytes has also been demonstrated functionally by Wang& Poo (1997).

Despite such evidence, major deficits remain in our understanding of howneurotrophin expression and release are regulated. Many of the experimentsdescribed above have relied on overexpression of neurotrophins in dissociatedcultures and release evoked by strong, nonphysiological stimuli such as chronicdepolarization and neurotransmitter application. It will be important in futureexperiments to study directly the release of endogenous neurotrophins by morephysiological stimuli.

REGULATION OF SYNAPTIC PLASTICITYBY NEUROTROPHINS

The efficacy of synaptic transmission can be modulated over a wide range oftemporal scales, ranging from synaptic modulation on the order of seconds tominutes (e.g. paired-pulse facilitation and post-tetanic potentiation; reviewedby Zuker 1989) to alterations that persist for many hours (e.g. LTP in hippocam-pus or LTD in the cerebellum; reviewed by Madison et al 1991, O’Dell et al1991, Hawkins et al 1993, Stevens 1993, Malinow 1994, Bear & Malenka 1994,Larkman & Jack 1995, Lisberger 1998, Stevens & Sullivan 1998). Still longer-lasting synaptic modifications over the time course of days to years presumablyoccur but remain poorly understood. Below, we consider some of the evidenceimplicating neurotrophins in plastic changes over a variety of these timescales.

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Acute Effects of Neurotrophins on Synaptic TransmissionKey evidence for short-term modulation of synaptic transmission was providedby Lohof et al (1993), who found strong effects of BDNF and NT-3 on synaptictransmission at developingXenopusneuromuscular synapses in culture. Acuteapplication of either BDNF or NT-3 to these cultures increases the frequency butnot the amplitude of spontaneous synaptic currents (mEPSCs) and the amplitudeof nerve-evoked excitatory postsynaptic currents (EPSCs) (Lohof et al 1993,Wang et al 1995). These effects are large (greater than sixfold increases forNT-3) and rapid (beginning within 5 min of neurotrophin application) anddepend on the continued presence of neurotrophin. More recently, Wang & Poo(1997) have shown that activity-dependent NT-4/5 secretion from transfectedmyocytes enhances acetylcholine release from presynaptic neurons.

Similar phenomena have also been reported for other CNS neurons. BDNFand NT-4 rapidly enhance spontaneous synaptic activity in dissociated culturesof hippocampal neurons (Lessmann et al 1994; Levine et al 1995b, 1996), whileNT-3 potentiates spontaneous activity in cultured cortical neurons (Kim et al1994). In biochemical measurements, NGF and BDNF enhance high potassium-induced release of acetylcholine and glutamate from hippocampal synapto-somes (Knipper et al 1994) and BDNF increases the expression levels of severalsynaptic vesicle proteins (Takei et al 1997) and promotes phosphorylation ofsynapsin 1 (Jovanovic et al 1996). Intriguingly, BDNF increases the phosphory-lation of NMDA receptors (Suen et al 1997) and alters the functional propertiesof NMDA receptor channels (Jarvis et al 1997). Finally, neurotrophins canrapidly elevate intracellular calcium levels (Berninger et al 1993, Stoop & Poo1996, Canossa et al 1997, Finkbeiner et al 1997, Jarvis et al 1997).

Neurotrophins also appear to affect several other aspects of synaptic trans-mission. BDNF influences neuropeptide expression in cortical neurons (Nawaet al 1993, 1994; Croll et al 1994) and in hippocampal interneurons (Martyet al 1996a,b), enhances the GABAergic phenotype in striatal and cortical neu-rons (Mizuno et al 1994, Widmer & Hefti 1994), acutely inhibits GABAergicsynaptic transmission in hippocampal slices (Tanaka et al 1997), and affectsactivity-dependent regulation of GABAergic neurons in neocortical cultures(Rutherford et al 1997). Finally, exogenous NGF and BDNF also cause rapidand long-lasting changes in stimulus-dependent activity in the adult cortex invivo (Prakash et al 1996).

In hippocampal slices, acute application of either BDNF or NT-3 potentiatessynaptic transmission at Schaffer collateral/CA1 synapses but does not occludeLTP (Kang and Schuman 1995), an effect that requires local protein synthesis(Kang & Schuman 1996). Such potentiation is not seen in all cases (Figurovet al 1996, Patterson et al 1996, Tanaka et al 1997, Huber et al 1998), an

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inconsistency that may be associated with the mode of BDNF delivery (Kanget al 1996). Similar effects have also been reported at other synapses in thehippocampus (Scharfman 1997, Messaoudi et al 1998), and BDNF and NGFboth acutely potentiate excitatory transmission in visual cortex (Carmignotoet al 1997).

Long-Term Potentiation and DepressionThe activity dependence and high-level of expression of BDNF and NT-3 in thehippocampus have led several groups to study their potential involvement in LTPand LTD, two especially well-studied models of synaptic plasticity. Despiteinitial observations that the rapid effects of neurotrophins do not occlude LTP(Kang & Schuman 1995), LTP induction at the hippocampal Schaffer collateral-CA1 synapse was found to be compromised in BDNF knockout mice (Korteet al 1995, Patterson et al 1996). These defects could be rescued either by trans-fection of hippocampal slices with a BDNF expressing adenovirus (Korte et al1996) or by application of exogenous BDNF (Patterson et al 1996). Moreover,in normal animals, inhibition of BDNF signaling with receptor bodies (TrkB-IgGs) or antibodies attenuates LTP in adult hippocampal slices (Figurov et al1996, Kang et al 1997), while BDNF enhances LTP in visual cortex (Akaneyaet al 1997).

One possible interpretation of these experiments is that BDNF signalingplays a permissive role in various aspects of hippocampal function includingLTP. It would then be expected that augmenting BDNF, regardless of its effectson basal synaptic transmission, would not occlude synaptically induced LTP.A permissive role would also predict that either genetic or pharmacologicalblockade of BDNF should inhibit LTP, as has been observed. Further supportingthis idea is the observation that exogenous BDNF promotes LTP in younghippocampal slices at ages when LTP is normally not inducible; it does soby improving the ability of presynaptic fibers to follow tetanic stimulation,consistent with a permissive role for BDNF (Figurov et al 1996).

Recent studies have begun to investigate the role of neurotrophins in LTD(Bear & Malenka 1994, Linden & Connor 1995, Bear & Abraham 1996).Induction of LTD in cerebellar slices increases the expression of BDNF (Yuzakiet al 1994), and, in the visual cortex, the induction of LTD by low-frequencystimulation is prevented by pretreatment with BDNF (Akaneya et al 1996,Huber et al 1998).

Neuronal ExcitabilityMembrane excitability is a major determinant of the intrinsic electrical prop-erties of neurons and is a key aspect of neuronal function involved in neuronalplasticity in both development and maturity. It also represents, along with

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neurite outgrowth, one of the most well-known regulatory targets of NGF.The robust effects of NGF on intrinsic electrical excitability have been studiedsince the mid-1970s; most of this work has been carried out with PC12 cellsand has focused on the expression levels of voltage-gated sodium and calciumcurrents (e.g. Greene & Tischler 1976; Dichter et al 1977; Rudy et al 1982,1987; O’Lague et al 1985; Streit & Lux 1987; Garber et al 1989; Kalman et al1990; Pollock et al 1990; Usowicz et al 1990; Baev et al 1992; Pollock & Rane1996; Sherwood et al 1997). The regulation of voltage-gated sodium channelsis known to be subtype specific and to occur at the transcriptional level (Mandelet al 1988, D’Arcangelo et al 1993, Toledo-Aral et al 1995). Similar regula-tion of voltage-gated sodium and calcium channels by NGF has been foundin neurons and skeletal muscle (Cooperman et al 1987, Levine et al 1995a,Toledo-Aral et al 1997). Finally, NGF and other neurotrophic factors also reg-ulate voltage-gated potassium channel expression (Sharma et al 1993, Dourado& Dryer 1994, Timpe & Fantl 1994, Lesser & Lo 1995, Bowlby et al 1997).

Studies of the influence of other neurotrophins on ion channel expressionhave provided an avenue for distinguishing between permissive and instructiveeffects of neurotrophin action on electrical excitability. In SK-N-SH neuroblas-toma cells, each neurotrophin increases the expression of unique subsets of theion channels normally expressed in these cells (Lesser et al 1997). Althougheach neurotrophin activates initial signal transduction cascades to equivalentlevels, each neurotrophin elicits a dramatically different end result on excitabil-ity. While NGF increases ion channel density similarly for all voltage-gated ionchannels, BDNF and NT-3 have different and opposite effects on ion channelexpression: BDNF increases excitability by selectively elevating sodium andcalcium channel expression, while NT-3 decreases excitability by selectively el-evating potassium channel expression. The unique effect of each neurotrophinon electrical excitability is consistent with an instructive role for neurotrophinsin regulating this aspect of neuronal function.

Results such as these strongly imply a central role for neurotrophic factorsin regulating electrical excitability, but a major limitation is that most of theexperiments discussed above have been done with neuronal cell lines. It will beimportant that similar experiments be carried out with functional neural circuitsand intact neural tissue to determine directly the functional consequences oftrophic regulation of ion channel expression.

NEUROTROPHINS AND STRUCTURALSYNAPTIC PLASTICITY

Structural changes in axonal and dendritic arbors are a hallmark of plasticrearrangements in developing systems; these lead to significant changes in

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the number and locations of functional synapses (Katz & Shatz 1996). Forexample, the activity-driven rearrangements that result in eye-specific layers inthe visual thalamus (Shatz 1983, Linden et al 1981, Sretavan & Shatz 1986, Pennet al 1998) and ocular dominance columns in visual cortex (Hubel & Wiesel1970; reviewed by Shatz 1990, Katz & Shatz 1996) involve the elaborationof synapses in one layer or column and the loss of synapses in other layersor columns. Local rearrangements on smaller scales have been implicated inplastic changes in the adult nervous system, such as lesion-induced plasticityin adult visual and somatosensory cortices (reviewed by Merzenich et al 1990,Gilbert et al 1996). Molecular signals that influence synaptic rearrangementsshould not only be able to modulate neuronal physiological properties but alsobe able to regulate the structure of axonal or dendritic arborizations (Bailey &Kandel 1993).

Neurotrophins seem especially well suited to be involved in such structuralchanges. In fact, NGF was isolated by its ability to stimulate neurite growth:Addition of an NGF-secreting sarcoma to an explant of chicken sensory gang-lion results in the emergence of a dramatic halo of neurites in only 12 h (Levi-Montalcini et al 1954). Subsequently, each neurotrophin has been demonstratedto stimulate neurite outgrowth of specific populations of neurons in the PNSin vitro and in vivo (reviewed by Thoenen 1991, Eide et al 1993, Lindsayet al 1994, Snider 1994). Recent studies have started to define more preciselythe nature and extent of these neurotrophin effects on axon pathfinding anddendritic growth in the CNS.

Axonal Branching and RearrangementsNeurotrophins can exert both tropic and trophic influences on axons. Althoughboth in vivo and in vitro experiments demonstrate that gradients of neurotro-phins can exert chemotropic guidance of axons (Menesini Chen et al 1978;Gunderson & Barrett 1979; Campenot 1982a,b; Ming et al 1997; Song et al1997), this may be a function of neurotrophins only in some cases. For example,NGF clearly does not play a role in guiding axons to their targets in developmentof trigeminal neurons, since NGF receptors are first detected on trigeminalneurons after their axons reach their targets (Davies 1990). Furthermore, thephenotypes of neurotrophin knockout mice (reviewed by Snider 1994) do notmanifest predictable deficits in axon pathfinding as they do for other knownchemotropic molecules (see, for example, Serafini et al 1996).

However, independent of their chemotropic effects, neurotrophins can po-tently influence the complexity of axonal arbors both in vitro and in vivo in theCNS. In vitro application of BDNF, NT-3, and NT-4/5, but not NGF, enhancesaxonal arborization of retinal axons cocultured with optic tecta from the chicken(Inoue & Sanes 1997). In vivo infusion of BDNF, but not other neurotrophins,

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into the optic tectum ofXenopustadpoles elicits substantial increases in thebranching and complexity of retinal ganglion cell axons (Cohen-Cory & Fraser1995). These effects are rapid (within 2 h) and persist for at least 24 h. Con-versely, injection of antibodies to BDNF prevents axon growth and reducesaxon complexity (Cohen-Cory & Fraser 1995).

Neurotrophins and the Control of Dendritic FormThe bulk of the brain’s neuropil is composed of dendrites. The location, branch-ing pattern, and morphological specializations of dendrites (spines, for exam-ple) are modified by activity and experience. Neurotrophins play a central rolein sculpting and modifying dendrites, both in the PNS and, as more recentfindings have shown, in the CNS.

Neurotrophins were first demonstrated to regulate dendritic growth in thePNS in an elegant series of experiments by Snider and colleagues (e.g. Snider1988, Purves et al 1988, Ruit et al 1990, Ruit & Snider 1991). Systemic treat-ment of neonatal and adult rats with NGF for 1–2 weeks results in a dramaticexpansion of dendritic arbors of sympathetic ganglion cells (Snider 1988, Ruitet al 1990). Conversely, injections of NGF antiserum in adult rats decrease thedendritic length of sympathetic neurons (Ruit & Snider 1991).

In the CNS, neurotrophins regulate the dendritic growth of pyramidal neuronsin the developing neocortex (McAllister et al 1995, Baker et al 1998). Forexample, each of the four neurotrophins, when applied to organotypic corticalslices for only 36 h, rapidly increases the length and complexity of dendritesof cortical pyramidal neurons (McAllister et al 1995). Neurons in each corticallayer respond to subsets of neurotrophins with distinct effects on basal andapical dendrites, and, within a single cortical layer, each neurotrophin elicits aunique pattern of dendritic changes (McAllister et al 1995). The specificity ofthese effects suggests that neurotrophins do not act simply to enhance neuronalgrowth but, rather, act instructively to modulate particular patterns of dendriticarborization.

One criticism of these and similar experiments, in which relatively high levelsof an exogenous factor are applied to a system, is that any phenomena producedby this manipulation may not reflect the normal levels or spatial distributionof endogenous signaling molecules. Therefore, it is especially important toassess whether endogenous neurotrophins can also regulate dendritic growth.Experiments involving Trk “receptor bodies” (Shelton et al 1995), which arefusion proteins of the ligand-binding domains of each Trk receptor and the Fcdomain of human IgG, clearly demonstrate that removing endogenous neu-rotrophins has dramatic consequences for the dendritic growth of pyramidalneurons in developing cortex (McAllister et al 1997). Consistent with the resultsof adding exogenous factors, endogenous BDNF is required for the growth and

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maintenance of dendritic arbors of layer 4 neurons whereas endogenous NT-3 isrequired for the growth and maintenance of dendritic arbors of layer 6 neurons.

Removing endogenous neurotrophins also reveals an added level of regula-tion not apparent from experiments in which exogenous factors were added.Endogenous BDNF (or possibly NT-4/5) and NT-3 oppose one another in reg-ulating dendritic growth: in layer 4, NT-3 limits dendritic growth caused byBDNF, while in layer 6, BDNF inhibits dendritic growth stimulated by NT-3(McAllister et al 1997). Thus, while neurotrophins have classically been con-sidered to act as growth-promoting molecules, it appears that they can also actto inhibit dendritic growth. The opposing roles of these two factors suggest thatthe well-documented overlap in neurotrophin signaling systems (e.g. the colo-calization of TrkB and TrkC and their respective ligands; see Lindsay et al 1994for a review) may not represent simple redundancy but, rather, may representthe outline of a tightly regulated system for modulating dendritic growth.

Synapse Number, Size, and MaturityIn addition to regulating the size of presynaptic terminal arbors and the extent ofpostsynaptic dendrites, target-derived neurotrophins have been widely hypoth-esized to regulate overall synapse number. This was first observed by Nja &Purves (1978) in the context of superior cervical ganglia, where manipulationof NGF levels regulated both the strength and number of preganglionic inputs.However, there are few other clear examples of direct effects of neurotrophins onsynapse number. In one recent example involving transgenic mice selectivelyoverexpressing BDNF in sympathetic neurons, electron microscopic counts ofthe synaptic innervation of sympathetic ganglia showed a two- to four-fold in-crease in synapse number; in BDNF knockout mice, synapse numbers werecorrespondingly decreased (Causing et al 1997). Indirect evidence that neu-rotrophins influence the maturation of functional synapses comes from studiesof the long-term effects of neurotrophins on synapses inXenopusnerve-musclecultures. BDNF and NT-3 but not NGF bias synaptic transmission and axonmorphology toward more mature phenotypes (Wang et al 1995). Furthermore,BDNF, NT-3, and NT-4/5 up-regulate neuregulin expression in rat spinal motorneurons, which promotes the maturation of neuromuscular synapses (Loeb &Fischbach 1997).

CAN NEUROTROPHINS TRANSLATE NEURONALACTIVITY INTO PHYSIOLOGICAL ANDSTRUCTURAL PLASTICITY?

Segregation of axons from the lateral geniculate nucleus (LGN) into oculardominance (OD) columns in layer 4 of the visual cortex and the manipulation

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of this process by selective visual experience has been a model system forstudies of activity-dependent developmental plasticity (Hubel & Wiesel 1970).The role of neurotrophins in activity-dependent competition during corticaldevelopment has been tested by using monocular deprivation during the criticalperiod for OD development. When animals are deprived of vision in one eyeduring a critical period, the axons and cell bodies of cortical projecting neuronsin the LGN shrink and neurons in the visual cortex become responsive to thenondeprived eye (see Wiesel 1982 for a review).

In early experiments, the physiological consequences of monocular depri-vation in young rats were prevented by global application of NGF by infusioninto the cerebral ventricles (Domenici et al 1991, 1993; Maffei et al 1992;Berardi et al 1993; Carmignoto et al 1993); conversely, anti-NGF antibodieswere shown to disrupt normal visual system development (Berardi et al 1994,Domenici et al 1994). These findings led Maffei and colleagues to propose thataxons from the LGN normally compete, in an activity-dependent manner, fora limiting supply of neurotrophin in layer 4 of the visual cortex. More recentexperiments have shown that focal injection of latex beads coated with NT-4/5but not those coated with BDNF, NT-3, or NGF into the visual cortex of mono-cularly deprived young ferrets prevents shrinkage of LGN neurons that projectto the deprived cortex (Riddle et al 1995, 1997). These results are also consis-tent with the hypothesis that LGN afferents compete in an activity-dependentmanner for limiting quantities of a neurotrophin in cortical layer 4 but suggestthat it is a TrkB ligand rather than NGF.

In recent experiments in which anatomical criteria were used to assess thedevelopment of OD columns, local infusion (via osmotic minipumps) of eitherBDNF or NT-4/5 but not NGF delayed or prevented the anatomical segregationof LGN afferents into OD patches (Cabelli et al 1995). Similarly, infusion ofTrkB-IgG fusion proteins, which remove endogenous BDNF or NT-4/5, but notof TrkA-IgG or TrkC-IgG also prevented segregation (Cabelli et al 1997). Oneplausible interpretation of these experiments is that either adding or removingexcess neurotrophin attenuates competition in layer 4 and thereby preventssegregation of LGN axons into OD columns (Cabelli et al 1997).

Thus, although there is an emerging consensus that neurotrophins are, atsome level, involved in the mechanisms of activity-dependent plasticity, thereis considerable controversy about both the identity and the mode of action ofthe active neurotrophin. Earlier work by Maffei and colleagues stressed therole of NGF (see also Gu et al 1994), whereas subsequent findings from otherlaboratories have generally supported a role for TrkB ligands (either BDNF,NT-4/5, or both) (Cobelli et al 1995, 1997; Riddle et al 1995, 1997; Galuske et al1996). Part of the controversy presumably results from significant differencesin choices of species, assays of effects, and methods of applying reagents.

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For example, most of the work suggesting a role for NGF involved injectionsof reagents into the ventricles, which allows diffusion throughout large areasof the brain. In contrast, most of the results implicating TrkB ligands wereobtained by more focal applications of neurotrophins or blockers. Both NGFand its receptor (TrkA) are expressed at very low levels, if at all, in the cortex(Merlio et al 1992, Allendoerfer et al 1994, Cabelli et al 1997). One possibleexplanation of the NGF results is that NGF is acting on cholinergic neurons inthe nucleus basalis, a structure rich in NGF and TrkA receptors, or their terminalarbors in the visual cortex, which also express TrkA receptors. However, it isalso possible that TrkA is present at very low levels in cortical neurons.

Comparing results from different laboratories is also complicated by thevery different measures of OD plasticity used. The bulk of the evidence for arole of NGF relies on electrophysiological assessments of OD, while the evi-dence for TrkB ligands (BDNF and NT-4/5) is largely anatomical. While somestudies have integrated particular anatomical and physiological approaches(Carmignoto et al 1993, Domenici et al 1993), no study has yet used the fullspectrum of electrophysiological and anatomical assays in a single well-definedmodel system.

CONCLUSIONS

The experiments reviewed here strongly suggest roles for neurotrophins insynaptic plasticity; however, the rules and mechanisms by which they work re-main intriguingly elusive. Several critical issues will have to be resolved beforehypotheses about neurotrophin function can be solidified. More thorough local-ization studies of the cellular and subcellular distribution of the neurotrophinsand their receptors, as well as the locations and mechanisms of their secre-tion, are clearly needed to advance our understanding of the potential roles thatneurotrophins might play in naturally occurring forms of synaptic plasticity.Such studies will be especially important in determining whether neurotrophinswork through synapse-specific mechanisms, a cornerstone of many models ofactivity-dependent plasticity.

Two other important areas of investigation are discussed below.

Retrograde versus Anterograde Actions of NeurotrophinsWhether neurotrophins act in retrograde or anterograde directions (or both) hasa clear impact on the specific forms of synaptic plasticity in which it is possiblefor them participate. The well-documented role of neurotrophins as target-derived, retrograde trophic factors in the PNS (Purves 1988, Oppenheim 1996,Snider 1994) has led many investigators to propose retrograde roles for neu-rotrophins in mediating synaptic plasticity in the CNS. Indeed, neurotrophins

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are retrogradely transported in both PNS and CNS neurons (Ernfors et al 1990,DiStefano et al 1992, Korsching 1993, Campenot 1994, Ehlers et al 1995,Oppenheim 1996, Bhattacharyya et al 1997). However, other studies haveshown substantial anterograde transport of neurotrophins in the CNS. Endoge-nous BDNF, for example, is prominently expressed in axon terminals, evenin brain regions that lack BDNF mRNA, and inhibition of axonal transport ordeafferentation depletes BDNF from these areas (Altar et al 1997, Conner et al1997, Yan et al 1997). Endogenous BDNF also appears to be anterogradelytransported in primary sensory neurons (Zhou & Rush 1996, Michael et al1997) and exogenous NT-3, injected into the eyes of developing chickens, canact as an anterograde signal, being taken up by retinal ganglion cells and trans-ported to axon terminals where it is then released and taken up by the dendritesof second-order visual neurons in the developing chicken brain (von Bartheldet al 1996). BDNF protein is also increased in mossy fiber terminals in thehippocampus following seizure induction, specifically in a vesicular fractionassociated with synaptic vesicles and dense core vesicles (Fawcett et al 1997,Smith et al 1997). This evidence, combined with several localization studiessuggesting that TrkB is present in dendrites of neurons in both hippocampusand cortex (e.g. Fryer et al 1997, Yan et al 1997), makes an anterograde func-tion for neurotrophins in synaptic plasticity at least as plausible as a retrogradefunction.

To complicate matters further, there is also increasing evidence for autocrineand paracrine roles of neurotrophins (Kokaia et al 1993, Korsching 1993,Miranda et al 1993, Acheson & Lindsay 1996, Davies 1996, Marty et al 1996a).Activity-dependent survival of cortical neurons in culture, for example, has beenshown to require the action of autocrine BDNF (Ghosh et al 1994).

Spatial and Temporal Specificity of Neurotrophin ActionDirect roles for neurotrophins in synaptic plasticity require precise spatial andtemporal regulation. Such specificity of action could be conferred temporallyby activity-dependent secretion and spatially by secretion exclusively fromsynaptic sites or by a limited synaptic distribution of Trk receptors (Wetmoreet al 1994, Thoenen 1995, Heymach et al 1996, Tongiorgi et al 1997, Molleret al 1998). However, at present there is little direct evidence of such regulationfor either neurotrophins or their receptors, as discussed above.

An alternative way to provide this specificity would be to require CNS neu-rons to be active in order to respond to neurotrophins, thereby allowing thetiming and sites of activity to determine the temporal and spatial specificityof neurotrophin action. In support of this idea, pyramidal neurons in slices ofdeveloping visual cortex must be active in order to respond to BDNF; inhibit-ing action potentials, glutamatergic synaptic transmission, or L-type calcium

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channel activity blocks the otherwise dramatic increases in dendritic arboriza-tions elicited by BDNF (McAllister et al 1996; but see Baker et al 1998). Also,depolarizing agents enhance the survival-promoting and morphological effectsof NGF on dissociated Purkinje cells (Cohen-Cory et al 1991) and those ofBDNF and other neurotrophic factors on the survival and dissociated retinalganglion cells (Meyer-Franke et al 1995).

Resolving these and other issues remains a high priority for understandinghow neurotrophins participate in various forms of synaptic plasticity. Nev-ertheless, it is exciting that we now have strong candidate molecular signalsfor mediating synaptic plasticity, especially over longer timescales that requirechanges in gene expression and neuronal connectivity.

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Annual Review of Neuroscience Volume 22, 1999

CONTENTSMonitoring Secretory Membrane with FM1-43 Fluorescence, Amanda J. Cochilla, Joseph K. Angleson, William J. Betz 1

The Cell Biology of the Blood-Brain Barrier, Amanda J. Cochilla, Joseph K. Angleson, William J. Betz 11

Retinal Waves and Visual System Development, Rachel O. L. Wong 29Making Brain Connections: Neuroanatomy and the Work of TPS Powell, 1923-1996, Edward G. Jones 49

Stress and Hippocampal Plasticity, Bruce S. McEwen 105Etiology and Pathogenesis of Parkinson's Disease, C. W. Olanow, W. G. Tatton 123

Computational Neuroimaging of Human Visual Cortex, Brian A. Wandell 145

Autoimmunity and Neurological Disease: Antibody Modulation of Synaptic Transmission, K. D. Whitney, J. O. McNamara 175

Monoamine Oxidase: From Genes to Behavior, J. C. Shih, K. Chen, M. J. Ridd 197

Microglia as Mediators of Inflammatory and Degenerative Diseases, F. González-Scarano, Gordon Baltuch 219

Neural Selection and Control of Visually Guided Eye Movements, Jeffrey D. Schall, Kirk G. Thompson 241

The Specification of Dorsal Cell Fates in the Vertebrate Central Nervous System, Kevin J. Lee, Thomas M. Jessell 261

Neurotrophins and Synaptic Plasticity, A. Kimberley McAllister, Lawrence C. Katz, Donald C. Lo 295

Space and Attention in Parietal Cortex, Carol L. Colby, Michael E. Goldberg 319

Growth Cone Guidance: First Steps Towards a Deeper Understanding, Bernhard K. Mueller 351

Development of the Vertebrate Neuromuscular Junction, Joshua R. Sanes, Jeff W. Lichtman 389

Presynaptic Ionotropic Receptors and the Control of Transmitter Release, Amy B. MacDermott, Lorna W. Role, Steven A. Siegelbaum 443

Molecular Biology of Odorant Receptors in Vertebrates, Peter Mombaerts 487

Central Nervous System Neuronal Migration, Mary E. Hatten 511Cellular and Molecular Determinants of Sympathetic Neuron Development, Nicole J. Francis, Story C. Landis 541

Birdsong and Human Speech: Common Themes and Mechanisms, Allison J. Doupe, Patricia K. Kuhl 567

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neurotrophins and synaptic plasticity · p1: kkk/vks/ary p2: ars/vks qc: ars december 10, 1998 14:8...

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