The Developing Synapse-Susana Cohen

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THE DYNAMIC SYNAPSE The Developing Synapse: Construction and Modulation of Synaptic Structures and Circuits Susana Cohen-Cory Synapse formation and stabilization in the vertebrate central nervous system is a dynamic process, requiring bi-directional communication between pre- and postsynaptic partners. Numerous mechanisms coordinate where and when synapses are made in the developing brain. This review discusses cellular and activity-dependent mechanisms that control the development of synaptic
  The Developing Synapse: Construction andModulation of Synaptic Structures and Circuits Susana Cohen-Cory Synapse formation and stabilization in the vertebrate central nervoussystem is a dynamic process, requiring bi-directional communicationbetween pre- and postsynaptic partners. Numerous mechanisms coordi-nate where and when synapses are made in the developing brain. Thisreview discusses cellular and activity-dependent mechanisms that controlthe development of synaptic connectivity. The function of the nervous system criticallyrelies on the establishment of precise synapticconnections between neurons and specifictarget cells (Fig. 1). During synaptogenesis,synapses form, mature, and stabilize and arealso eliminated by a process that requiresintimate communication between pre- and  postsynaptic partners. Most of our under-standing of synapse formation and stabiliza-tion comes from extensive studies performed at the neuromuscular junction (NMJ). How-ever, recent advances in methodologies thatinclude real-time imaging of living neuronshave provided insight into the molecular, cel-lular, and activity-dependent processes thatguide synaptogenesis in the developing cen-tral nervous system (CNS). This review high-lights several aspects of vertebrate synapto-genesis and its relation to activity-dependent processes, from the cellular mechanisms bywhich neurons communicate with each other to establish synaptic contacts to the role of activity during the development of topo-graphically ordered neuronal maps. Emphasisis placed on the development of central exci-tatory synapses, and some aspects of NMJdevelopment are also discussed. Synaptogenesis: A Microscopic View In the CNS, synapse assembly begins whenaxons approach their targets and establish con-tact with dendritic arbors or soma of their targetneurons. Real-time imaging experiments dem-onstrate that both axonal and dendritic filopodiaactively participate in synapse formation (Fig.2). Highly dynamic interactions at contact sitesof advancing axon growth cones and dendriticfilopodia have been demonstrated in living ze- brafish embryos in which pre- and postsynaptic partners were labeled with green fluorescent protein (GFP) ( 1 ). Highly motile dendriticfilopodia in zebrafish embryos resemble thoseof mammalian developing central neurons un-dergoing synaptogenesis both in culture ( 2 , 3 )and in vivo ( 4 ). Dynamic filopodia are also present in developing axon arbors before syn-apse differentiation ( 5  –  8 ) and have been impli-cated in synapse formation ( 9 ). Real-time im-aging of GFP-labeled synaptic components and functional imaging of presynaptic sites (labeled with FM 1-43, a vital dye that reveals activity-evoked synaptic vesicle recycling) have re-vealed the time course and sequence of eventsin CNS synaptogenesis. Imaging GFP-tagged synaptobrevin II (also known as VAMP II, asynaptic vesicle protein) in cultured hippocam- pal neurons revealed that transport packets con-taining preassembled synaptic vesicle compo-nents begin to accumulate at presynaptic sitesimmediately after axons and dendritic filopodiaestablish initial contact ( 10 ). Presynaptic com- ponents are assembled very rapidly, within 1 to2 hours of initial contact between neurons ( 10 , 11 ). Presynaptic differentiation is characterized  by the appearance of varicosities containingaccumulations of synaptic vesicles at the pre-synaptic side as well as by the onset of activity-evoked vesicle recycling ( 10 , 11 ). Real-timeimaging has also revealed that rapid changes in postsynaptic structures are also necessary for synaptogenesis to be initiated ( 1 , 2 , 4 , 12  –  14 ).The postsynaptic density protein 95 (PSD-95),the major component of the postsynaptic spe-cialization at glutamatergic synapses, hasserved as a useful postsynaptic marker of de-veloping synapses. Clustering of PSD-95 and glutamate receptor components at the postsyn-aptic site follows the functional and morpho-logical differentiation of presynaptic structuresin cultured hippocampal neurons ( 11 , 13 ) butoccurs simultaneously in cultured cortical neu-rons ( 9 ). Functional imaging of presynapticsites (labeled with FM 1-43), coupled withPSD-95 retrospective immunocytochemistry( 11 ) and dual color, simultaneous imaging of  pre-andpostsynapticcomponents(synaptophy-sin, a synaptic vesicle protein, and PSD-95)( 13 ), revealed that presynaptic differentiation precedes postsynaptic differentiation in devel-oping hippocampal neurons. Here, highly mo-tile dendritic filopodia were progressively re- placed by developing spines or protospines,which then matured into spines, tiny protru-sionsatwhichmostexcitatorysynapticcontactsare made ( 12 , 13 ). GFP–PSD-95 clusters wereabsentinfilopodiabutappearedcoincidentwithfilopodial differentiation into protospines and  became more abundant in mature spines ( 12 , 13 ), supporting the notion that filopodia and  protospines are precursors to mature, functionalglutamatergic synapses ( 2 , 3 , 15 ). In cultured cortical neurons, however, glutamate receptor– containing transport packets were rapidly re-cruited to axodendritic contact sites beforePSD-95 recruitment, forming functional syn-apses along the dendrite length ( 9 ). Thus, ex- perimental evidence indicates that rapid cellular and molecular events guide synaptogenesis inthe CNS. However, further studies are neces-sary to clearly differentiate between events thatguide the assembly of distinct synaptic circuitsversus perceived differences that arise fromlimitations in existing methodologies ( 16  ).The rapid dynamics of synapse assemblysupport the concept that synaptic remodelingmay accompany the morphological maturationof axonal and dendritic arbors. Thereby, thedynamic growth of axonal and dendritic arborsmay directly reflect the formation, stabilization,and elimination of synapses ( 17  , 18 ). A corre-late between synapse formation and dynamicremodelingofaxonarborstructurewasrecently provided by studies using GFP-tagged synapto- brevin to visualize synapse dynamics in ar- borizing axons in vivo . Simultaneous imagingof GFP-synaptobrevin clusters within individu-al Xenopus optic axons delineated by a red fluorescent dye (DsRed or DiI) demonstrated thatsynaptogenesisisadynamicprocessdirect-lycorrelatedtotheactivebranchingandremod-eling of axon terminal arbors ( 8 ). Along the branching axon arbor more synapses wereformed than eliminated, whereas a large pro- portion of synapses remained stable. Synapseformation in vivo occurs rapidly, in less than 2hours ( 8 ), supporting earlier in vitro observa-tions ( 10 , 11 ). Thus, the active remodeling of synapses is closely correlated to the dynamicchanges in axon arbor morphology, becauseaxon arborization and synapse formation and elimination occur at similar rates ( 6   –  8 , 19 ).How is synapse formation related to axonarborization and arbor structure? Visualizationof synaptic vesicle distribution along axon ar- bors in fixed tissues showed punctate synaptic protein localization along the entire extent of the arbor ( 20 , 21 ), suggesting that synapses areevenly distributed along the axon arbor. Elec-tron microscopy studies also revealed that ul- Mental Retardation Research Center, Department ofPsychiatry and Biobehavioral Sciences, University ofCalifornia, Los Angeles, Los Angeles, CA 90095, USA.E-mail: scohenco@ucla.eduPresent address: Department of Neurology and Be-havior, University of California, Irvine, Irvine, CA92697, USA. 25 OCTOBER 2002 VOL 298 SCIENCE 770T H E D Y N A M I C S Y N A P S ER E V I E W  trastructurally identified synapses are localized throughout the axon arbor ( 22 , 23 ), an observa-tion recently confirmed by in vivo imagingstudies ( 8 ). In more mature arbors, however,ultrastructurally identified synapses are prefer-entially localized to distal end branches ( 23 ). Invivo imaging studies further demonstrate thatGFP-synaptobrevin  –  labeled synaptic sites are preferentiallylocatedataxonbranchingsites.Infact, time-lapse imaging revealed a new aspectin the relation between axon branching and synapse formation: Almost all new branches(80.1  4.3%) srcinate at axon arbor sites richin synaptic clusters (Fig. 3) ( 8 ). Consequently,synapse formation and stabilization may be re-quired for new branch extension ( 24 ). The for-mation and stabilization of new synapses may,therefore, trigger the developmental, activity-dependent increase in axon arbor complexity( 19 , 25 , 26  ).During development, more synapses are es-tablished than ultimately will be retained.Therefore, the elimination of excess synapticinputs is a critical step in synaptic circuit mat-uration. Synapse elimination is a competitive process that involves interactions between pre-and postsynaptic partners. The dynamics of synapse formation ( 8 , 10 , 11 ) and of synapseelimination may be muchmorerapidintheCNSthanat the NMJ, where synapseelimination has been wellcharacterized. At the verte- brate NMJ, a single musclecell is initially innervated  by multiple motor axons.The transition from multi- ple innervation to innerva-tion by a single motor axonoccurs gradually as someterminal branches retractfrom each muscle fiber be-fore others, a process re-quiring about 24 hours for withdrawal of the presyn-aptic terminal ( 27  ). Motor axons lose branches asyn-chronously and withoutspatial bias ( 28 ), suggest-ingthatlocalinteractionsateachNMJregulatesynapseelimination. Synapse elim-ination at the NMJ is anactivity-dependent process,where weakening of syn-aptic function is thought to precede synapse disman-tling ( 29  –  31 ). Evidencefrom both the mammalianand  Drosophila NMJ indi-cates that presynaptic dis-assembly precedes disas-sembly of the postsynapticapparatus upon synapsedestabilization ( 28 , 32 ). Inthe CNS, as with the NMJ, a developmental,activity-dependent remodeling of synaptic cir-cuits takes place by a process that may involvethe selective stabilization of coactive inputs and the elimination of inputs with uncorrelated ac-tivity. The anatomical refinement of synapticcircuits occurs at the level of individual axonsand dendrites ( 33  –  35 ) by a dynamic processthat involves rapid elimination of synapses( 36  ). As axons branch and remodel, synapsesform and dismantle with synapse eliminationoccurring rapidly, in less than two hours ( 8 ). Invivo, the majority of branches destined to beeliminated do not express presynaptic markers beforetheirretraction.Thisobservation,togeth-er with the observation that most branches canestablish synapses regardless of whether theyare eventually stabilized or eliminated ( 8 ), sup- ports the notion that rapid synapse disassembly precedes branch elimination. Correlating func-tional imaging of synaptic sites (FM 1-43 im-aging) with presynaptic marker localization inculture hippocampal neurons in which gluta-mate receptor function was altered demonstrat-ed that synapse disassembly in the CNS occursrapidly, within 1.5 hours after synapses are nolonger functional ( 37  ). Removal of presynapticelements at central synapses thus occurs rapidlythrough an activity-dependent process, as dem-onstrated for the NMJ. Development of Synaptic Connectivity Many factors have been identified that influ-ence synapse formation and refinement in boththe NMJ and the CNS. Pre- and postsynapticdifferentiation are coordinated by anterogradeand retrograde interactions between the axongrowth cone and the target cell. Activity-dependent and -independent interactions guidethe initial steps of synapse differentiation and formation. Neural activity may play permissiverather than instructive roles during some as- pects of synaptogenesis. For example, at the NMJ, z -agrin is a key molecule that coordinates postsynaptic differentiation. Motor neurongrowth cones release z -agrin, a proteoglycanthat induces clustering of acetylcholine recep-tors (AChRs) and other postsynaptic compo-nents on the muscle fiber surface. Agrinactivates muscle-specific kinase (MuSK), atransmembrane receptor tyrosine kinase, and rapsyn, a membrane associated cytoplasmic protein also expressed in muscle ( 27  ). AChR clustering at the postsynaptic site is thought to be an activity-independent triggering event inneuromuscular synapse differentiation, because BasallaminaAChreceptorsPostsynapticmembraneGap junctionchannelsPostsynapticmembranePostsynapticneurotransmitterreceptorSynapticvesicle fusingSynapticcleft PostsynapticdensitySynaptic vesiclesActive zoneSchwanncellSynaptic vesiclesActivezone Muscle fiberJunctionalfoldsPresynapticmembranePresynapticmembrane Gap junction Presynapticmembrane A BC Fig. 1. Schematic representation of interneuronal and neuromuscular synapses. Synapses are asymmetric communica-tion junctions formed between two neurons, or, at the neuromuscular junction (NMJ), between a neuron and a musclecell. Chemical synapses enable cell-to-cell communication via secretion of neurotransmitters, whereas in less abundantelectrical synapses signals are transmitted through gap junctions, specialized intercellular channels that permit ioniccurrent flow. ( A ) At most interneuronal synapses, neurotransmitters are stored in synaptic vesicles and are released aftersynaptic vesicle fusion at the active zone (an event that is triggered by an action potential followed by a rapid influxof calcium into the presynaptic terminal). Neurotransmitter receptors and accessory molecules accumulate in thepostsynaptic membrane directly opposite the active zone in a postsynaptic membrane specialization known as thepostsynaptic density. ( B ) At electrical synapses, gap junctions between pre- and postsynaptic membranes permit currentto flow passively through intercellular channels. In addition to ions, other molecules that modulate synaptic function(such as ATP and second messenger molecules) can diffuse through gap junctional pores. Electrical synapses synchronizeelectrical activity among populations of neurons. ( C ) At the mature NMJ, pre- and postsynaptic membranes areseparated by a synaptic cleft containing extracellular proteins that form the basal lamina. Synaptic vesicles are clusteredat the presynaptic release site, transmitter receptors are clustered in junctional folds at the postsynaptic membrane, andglial processes surround the nerve terminal. SCIENCE VOL 298 25 OCTOBER 2002 771T H E D Y N A M I C S Y N A P S E  AChR clustering can occur at nerve-musclecontact sites in the presence of pharmacologicalactivity blockers, as well as in uninnervated muscle fibers. Further, AChRs aggregate inmuscle fibers of mice lacking all motor neuroninnervation, in patterns that closely resemblethose of innervated muscles ( 38 , 39 ). AChR clustering is, however, dependent on MuSK expression by the postsynaptic muscle fiber ( 38 , 39 ). Thus, initial phases of postsynapticdifferentiation can occur in the absence of thenerve. Such activity-independent differentiationand patterning of signals within the musclecell may serve to restrict synaptic innervation tothe center of the muscle fiber and to selectively promote axonal innervation at specific sites( 27  ). Though some aspects of postsynapticdifferentiation may occur independently of the presynaptic motor neuron, selective stabiliza-tion of AChRs at synaptic sites requiresneural-derived agrin, a process that is required for the activity-dependent maturation and stabilization of neuromuscular synapses( 27  ).Similar to the NMJ, neural activity may only beneededfromsomephasesofsynapseassemblyin the CNS. Synapse assembly may occur in theabsence of neurotransmission ( 40 , 41 ). Geneticdeletion of munc18-1, aneuron-specific proteinessential for synapticvesicle docking and neurotransmitter releasefromthepresynapticter-minal, completely abol-ishes neurotransmitter secretion and synaptictransmission, yet appar-ently normal structuralsynapses and neuronalcircuits form in theseknock-out mice ( 40 ).Further, neurotransmit-ter receptor clustering at postsynaptic sites canoccur under conditionsof chronic receptor  blockade ( 41 ), similarlysuggesting that activitymay not be required for initial aspects of synap-togenesis. However, nu-merous studies supportthe notion that some as- pects of synapse forma-tion and maturation re-quire activity. Evidencethat neurons are influ-enced by activity and secrete neurotransmit-ters at early stages of synaptogenesis supportsa role for activity in ear-ly synapse assembly.Axon growth conesnavigating toward their targets exhibit activesynaptic vesicle cycles and upregulate neuro-transmitter secretion once the growth cone ap- proaches its target ( 42 , 43 ). Additionally, neuralactivity modulates growth cone responsesto repulsive and attractive guidance cues( 44 ). The frequency and stability of initialaxon-dendritic filopodial contacts may also beinfluenced by neuronal activity, because den-dritic filopodial motility is modulated by depo-larization-inducedCa 2  influx( 1 ).Invivo,sen-sory deprivation that leads to reduction in ac-tivity can significantly influence dendriticfilopodial and spine motility during the crit-ical period of development, when developingneurons undergo synaptogenesis ( 4 ). Further support for a role for activity during initialsynapse formation comes from studies showingthat axonal and dendritic arborization are mod-ulated by action potential and synaptic activity( 19 , 25 , 26  , 34 , 45  –  50 ). Blocking synaptic activ-ity via the N  -methyl- D -aspartate NMDAsub-type of glutamate receptors (NMDARs)inhibits dendritic arbor growth of immature  Xenopus tectal neurons by preventing new branch addition ( 19 , 48 ), suggesting that NMDAR activation is required for early synapseformation. A distinct, stabilizing role for gluta-mate receptor activation inthe later phases of synapto-genesis and synapse matura-tion was suggested by stu-dies where blocking NMDAor   -amino-3-hydroxy-5-methyl-4-isoxazolepropri-onate (AMPA) receptor activity decreased dendrit-ic arbor size in morpholog-ically mature neurons ( 19 , 34 , 51 ). Metabotropic glu-tamate receptors may also participate in branch- and synapse-stabilizing re-sponses ( 52 ). In contrast,chronic NMDAR blockadein developing hippocampalslice cultures increasessynapse number during theearly period of synaptogen-esis ( 53 ). NMDAR-depen-dent changes resulted fromincreased dendritic num- ber and the corresponding increase in syn-apse number, without an increase in synapsedensity. Thus, experimental evidence sup- ports a role for synaptic activity in themodulation of axonal and dendritic arbor complexity and, therefore, synaptic com- plexity. Further studies are required, howev-er, to clearly distinguish how synaptic activ-ity, through activation of distinct neuro-transmitter receptors, differentially regulatessynapse formation versus stabilization indistinct neuronal populations. Lessons from Synaptic PlasticityModels Most evidence demonstrating a role for synaptic activity in the formation and mat-uration of synapses comes from studiesinvestigating synaptic structure and func-tion in synaptic plasticity models. Similar to the NMJ, the accumulation of neuro-transmitter receptors at the postsynapticneuron is a key feature in the developmentand remodeling of central synapses. Thesynaptic content of distinct neurotransmit-ter receptor subunits and distinct receptor subtypes are differentially regulated dur-ing synapse formation and maturation.For example, at glutamatergic synapses, NMDARs are developmentally expressed  before the expression of functional AMPAreceptors (AMPARs). Activity-dependentmechanisms control postsynaptic levels of neurotransmitter receptors, with differentmechanisms used for the synaptic targetingof NMDA and AMPA receptors ( 41 , 54  –  56  ). The translocation and clustering of  NMDARs at synaptic sites is inverselymodulated by NMDAR activity ( 56  , 57  ). NMDAR activation also induces redistribu-tion of AMPAR from intracellular pools tosynaptic sites ( 58 ), and AMPAR levels arealso dynamically regulated, with decreased activity increasing synaptic AMPAR con-tent ( 59 , 60 ). Rapid, activity-dependentsynaptic recruitment of AMPARs is asso-ciated with the functional maturation of excitatory “ silent ” synapses, characterized  by NMDAR currents but no AMPA cur-rents ( 58 ) . Interestingly, the developmentalmaturation of dendritic arbor morphology iscorrelated to the acquisition of AMPA synaptic Fig. 2. Stages in the development of interneuronal synapses. ( A and B ) An axongrowth cone approaches and interacts dynamically with a developing dendritethrough a two-way filopodial communication. ( C ) The pre- and postsynapticterminals form a morphologically unspecialized but functional contact. ( D )Synaptic vesicles begin to accumulate at the presynaptic terminal, triggeringneurotransmitter release and further synaptic differentiation. ( E ) Differentiationof the presynaptic terminal is followed by postsynaptic differentiation and bythe accumulation of membrane components (such as PSD-95) at the postsyn-aptic side. ( F ) The recruitment of organizing molecules like PSD-95 at thepostsynaptic specialization is followed by rapid neurotransmitter receptor ac-cumulation at that site and by the functional maturation of the synapse. A spinesynapse is used to illustrate the sequence of events during synapse develop-ment, but functional glutamatergic synapses can form along the dendrite shaftas well as in spineless dendrites. 25 OCTOBER 2002 VOL 298 SCIENCE 772T H E D Y N A M I C S Y N A P S E  currents ( 34 ). Glutamate re-ceptor expression is indepen-dentlycontrolledatindividualsynaptic sites, and spine mor- phology is correlated withglutamate receptor function.Filopodia and developingspines do not express func-tional AMPA receptors, ac-quiring AMPAR functionupon morphological matura-tionintoaspinesynapse( 61 ).These observations further support the suggestion thatactivefilopodiaareprecursorsto the morphological equiva-lent of silent synapses thatmature in an activity-depen-dent manner. Studies investigating theeffects of long-term synaptic plasticity have generallyused experimental para-digms in which repetitive,high-frequency stimulationgives rise to synaptic poten-tiation [long-term potentia-tion (LTP)] that is accompa-nied by structural and mo-lecular changes at the levelof single synapses. SuchLTP studies have revealed that NMDA-mediated syn-aptic activity triggers local-ized and rapid outgrowth of dendritic filopodia and newspine formation, morphological changesthought to correlate with the formation of new synapses ( 14 , 62 ). Recent imaging ex- periments reveal that both NMDA and AMPA receptor activation are indeed in-volved in synapse formation and matura-tion. Visualizing GFP-tagged actin dynam-ics in cultured hippocampal neurons re-vealed that specific neuronal stimulationinduces an active remodeling of pre- and  postsynaptic actin at existing synaptic sites,an event that relates to synaptic vesiclefusion ( 63 ). Additionally, the appearance of new presynaptic actin puncta was observed upon high-frequency stimulation. F-actin isan essential component of developing syn-apses, and neuronal activity can redistributeand stabilize synaptic F-actin ( 64 ). In partic-ular, NMDA and AMPA receptor blockers prevent presynaptic actin remodeling and therecruitment of new actin-labeled synapticsites ( 63 ). Thus, specific glutamate receptor activation leads to new synapse formation,further indicating that morphological and functional changes go together during the ac-tivity-dependent formation, maturation, and stabilization of central synapses. A number of cell adhesion moleculesand tyrosine kinase receptor ligands have been implicated in modulating synaptogen-esis largely by influencing synaptic func-tion. Integrins are required for the function-al maturation of hippocampal synapses invitro because they mediate a switch in NMDAR subunit composition from an im-mature form (NR2B) to a mature form(NR2B-NR2A) ( 65 ). Cadherins have also been implicated in synaptic targeting and synapse formation, and their adhesive prop-erties are themselves modulated by synap-tic function ( 66   –  69 ). Neuroligins, a largegroup of transmembrane cell adhesion mole-cules enriched in the postsynaptic membraneof glutamatergic synapses, are strong candi-date synaptogenic signals. Neuroligin-1alone, expressed in nonneuronal cells, trig-gered presynaptic differentiation in contact-ing axons by binding to  -neurexins ( 70 ).The ephrins and their receptors, the Eph ty-rosine kinases, participate in the activity-in-dependent topographic organization of braincircuits ( 71 ) and may also participate in syn-apse formation and maturation by modulating NMDAR function ( 72 , 73 ). Neurotrophinshave been implicated in multiple aspects of synapse development and function, and evi-dence supporting their role in synaptogenesisis briefly discussed below. Neurotrophins asSynaptic Modulators  Neurotrophins, a family of neuronal growth factorsthat includes nerve growthfactor (NGF), brain-de-rived neurotrophic factor (BDNF), neurotrophin 3(NT-3), and neurotrophin4/5 (NT-4/5), are candidatemolecules to modulatesynaptogenesis in the de-veloping brain. Thoughneurotrophins were initial-ly characterized for their roles in promoting neuro-nal survival and differenti-ation, they also participatein many aspects of synapsedevelopment and function( 74 ). Neurotrophins haveemerged as key signals thatmediate activity-dependentfunctional and structu-ral plasticity in both theembryonic and mature brain ( 74  –  78 ). Neurotro- phins may act as retro-grade signals influencing presynaptic neurons, aswell as anterograde factorsacting on postsynapticcells ( 79 ). Electrical activ-ity and sensory input activ-ity modulate both neuro-trophin expression and re-lease ( 80 ). The specific, activity-dependentvesicular release of BDNF from postsynapticsites ( 81 ) and the BDNF-induced protein syn-thesis in dendrites ( 82 ) suggest that neurotro- phins can exert their effects at the level of individual synapses. Neurotrophin tyrosinekinase receptors themselves accumulate atsynapses (both presynaptically and postsyn-aptically) ( 83 , 84 ) with their activation ( 85 )and translocation to the membrane ( 86  ), de- pending on activity. Neurotrophins can pro-foundly influence axon and dendritic mor- phology and dendritic spine stability in de-veloping neurons ( 77  , 87  ), suggesting thatthey play important roles in the developmentof neuronal connectivity. In particular, BDNFhas emerged as a key player in the develop-ment of neuronal connectivity. BDNF modu-lates axonal and dendritic branching and re-modeling ( 6  , 88  –  94 ), increases the efficacyof synaptic transmission ( 95  –  98 ), modulatesthe functional maturation of inhibitory and excitatory synapses ( 99  –  101 ), and is involved in the maturation and plasticity of neuronalnetworks ( 78 , 102  –  104 ). Thus, BDNF may be required for synapse formation and stabi-lization ( 17  , 74 , 75 ). Studies in transgenicmice demonstrate that target-derived BDNFregulates the expression of synaptic vesicle Fig. 3. Visualizing synapse formation in arborizing axons in vivo. ( A to C ) Dual-colorimaging of GFP-synaptobrevin and DsRed labeled optic axons in living Xenopus tadpoles illustrates the relation between synapse formation and distribution andaxon branch dynamics. Time-lapse confocal microscope images of portions ofindividual arbors show that new branches srcinate at axon arbor sites rich inGFP-labeled synaptic clusters [white arrows in (A) to (C)] as well as the recruitmentof new GFP-labeled synaptic clusters [(B), arrowhead] along an axon branch. Scalebars, 10  m. SCIENCE VOL 298 25 OCTOBER 2002 773T H E D Y N A M I C S Y N A P S E
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