The role of ECM molecules in activity-dependent synaptic development and plasticity

The Role of ECM Molecules in Activity-DependentSynaptic Development and Plasticity

Ivan Pavlov, Sari Lauri, Tomi Taira,* and Heikki Rauvala

INTRODUCTIONThe perinatal period of the mam-malian central nervous system(CNS) is characterized by intensedifferentiation of the dendritic treeand concomitant development ofexcitatory synapses. In parallel, in-termittent electrical activity can berecorded in the developing neuro-nal network (Donovan, 1999; Ben-Ari, 2001). Apart from starting tobe able to respond to synaptic in-puts (e.g., sensory stimuli), theemerging network is also capable ofgenerating endogenous activitypatterns. It is now widely acceptedthat not only are electrical activityand the coinciding synaptogenesistemporally correlated, but that theactivity may be instrumental in theformation of synaptic contacts. Ev-

idently, the conversion of transientelectrical signals into persistentmodifications in synaptic structurerequires intimate coupling betweenelectrical and molecular signalingwithin the neuron and its microen-vironment. For example, in the hip-pocampus, development of thesynaptic circuitry involves a grad-ual increase in the synaptic connec-tivity, which is seen both anatomi-cally and functionally (Fiala et al.,1998; Hsia et al., 1998). In parallel,the synapses establish maturestructural and functional character-istics by recruitment of molecularcomponents to the pre- andpostsynaptic sites.

Refinement of synaptic connec-tivity involves cooperative andcompetitive interactions between

converging inputs, leading to stabi-lization or elimination of the imma-ture connections (Zhang and Poo,2001). This process is thought toemploy mechanisms similar tothose used in the adult brain for ac-tivity-dependent regulation of syn-aptic efficacy, namely long-termpotentiation (LTP) and long-termdepression (LTD). It is well estab-lished that the induction of LTP/LTDis critically dependent on spatio-temporally correlated activity ofthe pre- and postsynaptic cells(Markram et al., 1997; Bi and Poo,1998; Zhang et al., 1998). It hasrecently been shown, both in vivoand in vitro, that the spontaneousactivity, e.g., in the developing hip-pocampal circuitry, is comprised oflocally synchronous high-frequencybursts, and is thus suitable for mil-lisecond range temporal integrationin the developing network (Palva etal., 2000; Khazipov et al., 2001;Lahtinen et al., 2002). There is nowever-increasing evidence demon-strating that this type of activity iscritical in maintaining the dynamicbalance between synaptic assem-bly and disassembly in the develop-ing hippocampus (Lauri et al.,2003), as well as in other areas ofthe developing nervous system(Katz and Shatz, 1996; Lohmann etal., 2002).

Here, one of the key questions is:What are the molecular mecha-nisms that detect the neuronal ac-tivity patterns, and link them tofunctional and structural changesat the synapses? Recent studies

Growth and guidance of neurites (axons and dendrites) duringdevelopment is the prerequisite for the establishment of functional neuralnetworks in the adult organism. In the adult, mechanisms similar to thoseused during development may regulate plastic changes that underlieimportant nervous system functions, such as memory and learning. Thereis now ever-increasing evidence that extracellular matrix (ECM)-associated factors are critically involved in the formation of neuronalconnections during development, and their plastic changes in the adult.Here, we review the current literature on the role of ECM components inactivity-dependent synaptic development and plasticity, with the majorfocus on the thrombospondin type I repeat (TSR) domain-containingproteins. We propose that ECM components may modulate neuronaldevelopment and plasticity by: 1) regulating cellular motility andmorphology, thus contributing to structural alterations that are associatedwith the expression of synaptic plasticity, 2) coordinating transsynapticsignaling during plasticity via their cell surface receptors, and 3) definingthe physical parameters of the extracellular space, thereby regulatingdiffusion of soluble signaling molecules in the extracellular space (ECS).Birth Defects Research (Part C) 72:12–24, 2004.© 2004 Wiley-Liss, Inc.

Ivan Pavlov, Sari Lauri, Tomi Taira, and Heikki Rauvala are from the Neuroscience Center and Department of Biosciences,University of Helsinki, Helsinki, Finland.

*Correspondence to: Dr. Tomi Taira, Neuroscience Center and Department of Biosciences, University of Helsinki P.O. Box 65 (Viikinkaari1), FIN-00014, Helsinki, Finland. E-mail: [email protected]

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdrc.20001

REVIE

WBirth Defects Research (Part C) 72:12–24 (2004)

© 2004 Wiley-Liss, Inc.

have pointed out the importance ofcell surface adhesion molecules,soluble growth factors, and in par-ticular, extracellular matrix (ECM)-associated factors, in the formationof functional neuronal connectionsduring development, as well as inneuronal plasticity in the adult(e.g., Luthi et al., 1994; Lauri et al.,1998; see also Dityatev andSchachner, 2003). These mole-cules mediate transsynaptic signalsin response to neuronal activity inorder to coordinate simultaneouspre- and postsynaptic development(e.g., Contractor et al., 2002).

ECM in the Brain Tissue:Structure and Functions

The ECM accounts for a relativelylarge volume of the nervous tissue.On average, it has been estimatedto occupy about 20% of the brainin adults, and twice as much innewborn animals (Nicholson andSykova, 1998). The structure of theECM is highly organized, and con-sists of a number of components.

Collagens, along with noncollag-enous glycoproteins (fibronectin,laminins, vitronectin, thrombo-spondins, and tenascins), form theadhesive substrate necessary forneuronal migration and morpho-genesis during development. Theyalso provide the molecular networkto maintain mechanical support forthe cells in the brain tissue. As anadhesive substrate for cell-surfacemolecules such as integrins, theECM is critical for the regulation ofcell shape and motility (Suter et al.,1998; Nikonenko et al., 2003). Inthe nervous system, the ECM is cru-cial for many developmental pro-cesses such as neuronal migration,neurite outgrowth, growth coneguidance, and synapse formationand stabilization (Ruegg, 2001). Inthe adult brain, numerous studieshave demonstrated the role of ECMin neuropathological conditions(Knott et al., 1998; Bruckner et al.,1999; Gutowski et al., 1999; Sobeland Ahmed, 2001), as well as inphysiological processes like synap-tic plasticity (reviewed by Dityatevand Schachner, 2003).

Two major categories of proteo-glycans present in the ECM seem

to be linked to these functions:chondroitin sulfate proteoglycans(CSPGs) and heparan sulfate pro-teoglycans (HSPGs) (reviewed byBandtlow and Zimmermann, 2000;Hartmann and Maurer, 2001).Among the best characterizedCSPGs and HSPGs in the ECM are:aggrecan, brevican, neurocan, ver-sican, and phosphacan; and agrin,glypican, cerebroglycan, perlecan,and syndecans, respectively. Mostof the functions of the proteogly-cans are mediated by their glycos-aminoglycan side chains, whichbind to various signaling factorsand cell-surface molecules. In addi-tion to the integral components ofthe ECM, several secreted growth/differentiation factors, e.g., fibro-blast growth factors (FGFs) and he-parin-binding growth-associatedmolecule (HB-GAM), are present inthe extracellular space. The biolog-ical activity of these factors can becritically modulated by their inter-action with the ECM components.For example, heparan sulfate is es-sential for the biological activities ofthe FGFs (Raman et al., 2003).

In the brain, the functional role ofthe ECM extends beyond the regu-lation of cellular morphology. Theextracellular space serves as a low-resistance conducting media for thetransmembrane currents createdby neuronal activity. By this virtue,the ECM regulates the diffusion ofions, neurotransmitters, and otherneuroactive substances in the ex-tracellular space (Nicholson andSykova, 1998). For example, themain neurotransmitters GABA andglutamate bind not only to thepostsynaptic receptors that medi-ate fast neurotransmission, butalso to presynaptic auto- and het-ero-receptors that regulate theprobability of neurotransmitter re-lease, and thereby the short-termdynamics of synaptic transmission.Activation of presynaptic and extra-synaptic receptors is dependent onneurotransmitter “spillover,” whichis regulated by active uptake mech-anisms but also by the tortuosity ofthe extracellular space. Conse-quently, changes in the ECM com-position can critically influence syn-aptic efficacy, neuronal excitability,synapse specificity, and volume

transduction in the brain (Min et al.,1998; Kullmann et al., 1999).

DYNAMIC REMODELING OFECM IN THE NERVOUSSYSTEM

The ECM is no longer seen as astatic embedding in which cells re-side. The composition of the ECM isconstantly being modified through-out life in both the peripheral ner-vous system (Sanes et al., 1986;Connor, 1997), as well as in theCNS (e.g., Fuss et al., 1993; Ferhatet al., 1996; Yamaguchi, 1996;Koppe et al., 1997). Given thenumber of neuronal functions influ-enced by the ECM, its remodelingduring development, in response tophysiological stimuli and underpathological conditions, provides apowerful mechanism for structuraland functional regulation of ner-vous tissue.

The physical parameters of extra-cellular space in the brain arealtered in several pathologicalconditions and following neuronaltrauma (reviewed by Sykova et al.,2000). For example, peripheralnerve axotomy causes an upregu-lation of floor plate gene (F-spondin) mRNA and protein levels(Burstyn et al., 1998). HB-GAM,agrin, glypican, and syndecans ac-cumulate in amyloid plaques in Alz-heimer’s disease (Wisniewski et al.,1996; Verbeek et al., 1999; van-Horssen et al., 2002). HSPGs weresuggested to play an important rolein the formation and persistence ofsenile plaques. A number of differ-ent CSPGs are increased in the ner-vous system at the region wherethe glial scar forms following the le-sion. Upregulation of these mole-cules is believed to restrict axonalregeneration at the site of injury(Zuo et al., 1998; Morgenstern etal., 2002; Properzi et al., 2003).

Furthermore, regulation of ECMcomponents in response to neuro-nal activity might provide a way forphysiological regulation of neuronalexcitability, plasticity, and syn-chrony. In fact, expression of sev-eral ECM components is regulatedin response to neural activity pat-terns. For example, Narp (synapticpentraxin enriched at glutamater-

ECM IN SYNAPTIC DEVELOPMENT AND PLASTICITY 13

Birth Defects Research (Part C) 72:12–24, (2004)

gic synapses on most aspiny, butnot spiny, hippocampal and spinalcord neurons) was originally clonedas an immediate-early gene, rap-idly induced in neurons by high-fre-quency stimulation (HFS) or re-peated electroconvulsive seizures(Tsui et al., 1996; Reti and Bara-ban, 2000). Agrin expression in theCNS, particularly in hippocampalneurons in vivo, has been demon-strated to be regulated in an activ-ity-dependent manner (Connor etal., 1995; Cohen et al., 1997; Lesu-isse et al., 2000). Effects of activityblockade on agrin expression de-pends on the degree of synapsematuration. Action potential-de-pendent neurotransmission block-ade at early and late phases of syn-apse maturation had contrastingeffects on the level of agrin mRNA(Lesuisse et al., 2000). In addition,agrin has been demonstrated to ac-tivate immediate early gene c-fos incortical neurons through the Ca2�-dependent mechanism (Hilgenberget al., 1999, 2002). Among otherECM and cell-adhesion moleculesexpressed in activity-dependentmanner are HB-GAM (Lauri et al.,1996), tenascin C (Nakic et al.,1996, 1998), N-cadherin, NCAM,and L1 (Itoh et al., 1995, 1997).

In addition, fast activity-inducedchanges in the composition of ECMmight be obtained by the activityof extracellular proteases. Matrixmetalloproteinases (MMPs) are thegroup of ECM degrading enzymesthat play a crucial role in neural mi-gration, development, growth, andrepair by matrix remodeling (Sha-piro, 1998). There is accumulatingevidence that the balance of MMPsand their tissue inhibitors (TIMPs)play an important role in brain func-tion, as they have been implicatedin a number of neural diseases (re-viewed in Lukes et al., 1999; Skileset al., 2001). Activity-dependentmechanisms of regulation havebeen demonstrated for both the ac-tivity of MMP (Jourquin et al., 2003)and tissue-type plasminogen acti-vator (tPA) (Qian et al., 1993; Gua-landris et al., 1996). Thus, undernormal conditions, changes in theactivity of MMPs may contribute tothe expression of synaptic plastic-ity, and affect learning and memory

(Wright et al., 2002). However, thephysiological significance of thesemechanisms is only beginning to beunderstood.

ECM ANDSYNAPTOGENESIS

Neuromuscular Junction

Much of our knowledge on the roleof ECM molecules in synapse for-mation is based on studies of theneuromuscular junction (NMJ). Thecritical role of the basal lamina inpostsynaptic differentiation at thissynapse has been long recognized(Burden et al., 1979; McMahan andSlater, 1984), and can largely beexplained by the biological activityof agrin (McMahan, 1990). First iso-lated from Torpedo electric organ(Godfrey et al., 1984; Nitkin et al.,1987), agrin is an HSPG synthe-sized by motor neurons, trans-ported down to motor axons, andreleased from motor terminals toincorporate into basal lamina of thesynaptic cleft. Agrin, its receptorMuSK, and the cytoplasmic protein,rapsyn (downstream of MuSK in thecell-signaling agrin pathway) areprimarily needed for postsynapticinduction in the NMJ (Bowe and Fal-lon, 1995; Sanes et al., 1998;Ruegg, 2001).

Mutant mice studies indicate thatlack of either of these signalingmolecules results in a profound im-pairment in NMJ synaptogenesis(Gautam et al., 1995, 1996, 1999;DeChiara et al., 1996; ). However,although postsynaptic organizationis markedly reduced in agrin knock-out mice, muscle cells still containAChR clusters, both at the nonin-nervated postsynaptic membraneand at the NMJ, indicating thatother mechanisms of synaptic or-ganization exist (e.g., Sugiyama etal., 1997). Besides agrin, severalother ECM components, includingFGF, HB-GAM, laminin, and mid-kine, have been shown to act asclustering agents at the NMJ (Penget al., 1991, 1995; Rauvala andPeng, 1997; Sugiyama et al., 1997;Zhou et al., 1997; Montanaro et al.,1998). These ECM signaling mole-cules can alter, amplify, or triggerinitial agrin effects, utilizing either

their own signaling machinery orconvergent pathways (Burkin etal., 2000; Bixby et al., 2002; Lee etal., 2002). Thus, this suggests thatsuch modulatory mechanisms forthe agrin signaling pathway mightbe used for regulation of synapseinduction by external physiologicalstimuli, for example, in the fine-tuning of the synaptic assembly inresponse to neuronal activity.

At the NMJ, it appears thatpostsynaptic differentiation is aprerequisite for the induction of thepresynaptic nerve terminal. Al-though the signals involved havenot been clearly defined, laminin �2(s-laminin) is possibly one of suchretrograde signaling factors. Stud-ies of knockout mice lacking s-lami-nin revealed that maturation ofnerve terminals is severely im-paired; synaptic vesicles fail to ag-gregate, few active zones areformed, and the level of synaptictransmitter release is decreased(Noakes et al., 1995). Coordinateddevelopment of pre- and postsyn-aptic specializations appears to re-lay on anterograde and retrogradetranssynaptic signaling. Reciprocalinteractions, mediated by diffusiblemessengers and/or adhesion fac-tors, seems to be crucial for the dif-ferentiation and stabilization of thesynaptic contacts (reviewed by,e.g., Tao and Poo, 2001; Goda andDavis, 2003).

CNS SYNAPSES

So far, a factor like agrin, which isabsolutely essential for synapseformation in the CNS, has not beenidentified. However, given thestructural and functional diversityof the central synapses, this is notsurprising. Compared to the NMJ,where mainly ACh is used as atransmitter, the central neurons re-ceive multiple types of input, andmust target the appropriate set ofpostsynaptic receptors to each typeof synapse. The requirement oftransmitter specific receptor tar-geting is reflected in the contribu-tion of early neurotransmitter me-diated signals in synapse induction(e.g., Kirsch and Betz, 1998; Leviet al., 1998; Brunig et al., 2002;Tashiro et al., 2003). However, the

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following differentiation of the pre-and postsynaptic specializations re-quires transsynaptic signaling thatinvolves cell adhesion and ECM (re-viewed by Garner et al., 2002;Goda and Davis, 2003; Scheiffele,2003).

Several cell-surface and extracel-lular factors have been shown to in-duce synaptic differentiation in cen-tral neurons, and include Narp,neuroligins, SynCAM, syndecans,Eph-receptors, cadherins, and inte-grins (Benson and Tanaka, 1998;Ethell and Yamaguchi, 1999; Dalvaet al., 2000; Scheiffele et al., 2000;Ethell et al., 2001; Biederer et al.,2002; Togashi et al., 2002; Ni-konenko et al., 2003; Xu et al.,2003). In addition, agrin, as well asmany of the ECM components thatbind agrin in the NMJ, are also ex-pressed in the CNS, and includelaminin, HB-GAM, FGF-2 (bFGF),and thrombospondin (Matsuyamaet al., 1992; Wanaka et al., 1993;Gomez et al., 1994; Hoffman et al.,1994; Cohen et al., 1997; Chen etal., 2003; Indyk et al., 2003). How-ever, none of the identified individ-ual molecular signals is essential forsynapse formation, e.g., in geneknockout studies, suggesting re-dundancy in the mechanisms. Thepresence of partially redundantpathways makes the process ofsynapse development not only veryrobust, but also flexible enough toadapt to changes in synaptic trans-mission, and reorganize synapticconnections in response to physio-logical stimuli (Goda and Davis,2003; Scheiffele, 2003).

ECM AND ACTIVITYDEPENDENT SYNAPTICPLASTICITY

It is becoming increasingly evidentthat activity-induced synaptic plas-ticity in the brain involves changesin neuronal morphology (e.g., Toniet al., 2001; Weeks et al., 2003;reviewed by Yuste and Bonhoeffer,2001; Marrone and Petit, 2002;Harris et al., 2003). Initially, struc-tural alterations were proposed tobe necessary for long-term mainte-nance of functional changes in syn-aptic efficacy (Fifkova and Ander-son, 1981; Schuster et al., 1990;

Buchs and Muller, 1996; Toni et al.,1999; Ostroff et al., 2002), basedon the findings that late, but notearly, phases of LTP are dependenton protein synthesis and gene tran-scription. The first ECM receptorsreported to be involved in the reg-ulation of hippocampal LTP werethe integrin type of cell-adhesionmolecules. Blockade of extracellu-lar interactions of integrins inhibitsexpression of LTP 40 min after itsinduction (Xiao et al., 1991; Bahr etal., 1997). Inhibition of other cell-matrix receptors, including PSA-NCAM (Luthi et al., 1994; Ronn etal., 1995; Muller et al., 1996), cad-herins (Tang et al., 1998), and syn-decans (Lauri et al., 1999) affectsexpression of LTP even faster, con-sistent with rapid remodeling ofsynaptic structures in responseto neuronal activity (Segal andAndersen, 2000; Dunaevsky et al.,2001; Bonhoeffer and Yuste, 2002;Dunaevsky and Mason, 2003).

The manipulations of ECM inter-actions do not seem to influencebaseline synaptic transmission.This is consistent with a “passive”role of ECM receptors as an inhibi-tory constraint for synaptic remod-eling and/or growth in response tosignals inducing synaptic plasticity(reviewed by Fields and Itoh, 1996;Abel et al., 1998). According to thisview, downregulation of cell-adhe-sion is necessary for high frequencystimulation (HFS)-induced plasticchanges in synaptic function andmorphology. Proposed mecha-nisms for reduction of cell adhesionin synaptic plasticity include inter-nalization or proteolytic cleavage ofthe cell-surface ECM receptors(Mayford et al., 1992; Fazeli et al.,1994; Liu et al., 1994; Nakagami etal., 2000; Bukalo et al., 2001), andcalcium dependent downregulationof cadherin-mediated adhesion(Tamura et al., 1998; Tang et al.,1998). Cleavage or shedding of HS-proteoglycans in response to neu-ronal activity might represent asimilar regulation mechanism (Su-giura and Dow, 1994; Asundi et al.,2003).

Instead of merely acting as astructural limit, an active role forECM components and cell surfaceECM receptors in regulation of syn-

aptic transmission has been pro-posed. This more recent view issupported by several findings.

Narp selectively interacts withthe a-amino-3-OH-5-methyliox-azolate-4-propionic acid (AMPA)receptor subunits GluR1-3, and di-rectly affects receptor clustering(Brien et al., 1999, 2002; Fong andCraig, 1999; Xu et al., 2003), amechanism proposed to be criticalfor expression of LTP (Malinow andMalenka, 2002). Also, heparin hasbeen reported to bind AMPA recep-tors and alter kinetic properties ofsingle channel activity (Hall et al.,1996; Sinnarajah et al., 1999).Thus, it is possible that ECM com-ponents can directly affect func-tional properties of AMPA recep-tors. On the other hand, tenascin-Rand tenascin-C bind voltage-gatedsodium channels, and have beensuggested to play an important rolein modulation of their activity andlocalization in neurons (Xiao etal., 1999; Srinivasan et al., 1998).In addition, tenascin-C has beenimplicated in L-type voltage-dependent Ca2� channel-mediated(VDCCs) signaling (Evers et al.,2002). ECM molecules were alsodemonstrated to affect GABAergictransmission. Tenascin-R and itsassociated carbohydrate, HNK-1,modulate perisomatic inhibition inthe hippocampus via regulation ofGABA release in perisomatic syn-apses suppressing postsynapticGABA-B receptor activity (Saghat-elyan et al., 2000, 2001, 2003).

In addition, transmembrane pro-teins, which bind ECM components,might act as independent signalingreceptors to mediate activity-induced changes. LTP-inducedchanges in the interaction of the cy-tosolic domain of syndecan-3, afunctional receptor of heparin-binding growth-associated mole-cule (HB-GAM), with intracellularsignaling molecules, have been re-ported (Lauri et al., 1999) within 10min after induction of LTP in areaCA1 in the hippocampus; associa-tion of syndecan-3 with the tyrosinekinase, fyn, and an actin-bindingprotein, cortactin, was significantlyincreased, suggesting a role for thissignaling complex in the mecha-nisms of LTP expression. Also, spe-



cific signaling, which involves pro-tein kinases Fnk and Snk, has beenproposed for laminin receptorsintegrins during LTP induction(Kauselmann et al., 1999).

HB-GAM AND TSR DOMAINPROTEINS IN NEURONALDEVELOPMENT ANDPLASTICITY

One of the ECM proteins implicatedin both the developmental forma-tion of neuron-target contacts andin neuronal plasticity in the adulthippocampus is HB-GAM. HB-GAM,also known as pleiotrophin (Ptn) (Liet al., 1990), is a secreted 18-kDprotein that is associated with theHS-containing proteoglycans of thecell-surface and ECM (Rauvala,1989). The amino acid sequence ofHB-GAM is highly conserved acrossvertebrate species and folds into astructure containing two beta-sheet domains connected by a flex-ible linker (Iwasaki et al., 1997;Kilpelainen et al., 2000). These do-mains consist of three antiparallelbeta strands, and show significanthomology to the thrombospondintype I repeats (TSR) that are foundin several cell-surface and ECM pro-teins (Kilpelainen et al., 2000).

TSR domains share a commonproperty of binding to heparin andHS, and the presence of these re-peats probably defines biologicalfunctions and properties of the par-ticular protein (reviewed by Naitzaet al., 1998). Currently, availablefunctional data suggest that thefamily of TSR proteins is specializedin cell surface and matrix binding.For example, several proteins thathave been implicated in neuritegrowth and guidance during thelast few years contain TSR repeats.F-spondin was initially identified asan axon growth and guidance factor(Klar et al., 1992). Other examplesof neurite-promoting TSR domainproteins include midkine (MK),UNC-5, thrombospondin-1 (TSP-1), and semaphorins F and G(Kilpelainen et al., 2000). We havethus suggested that the TSR do-main provides one basic cell sur-face-binding protein module that isinvolved in neurite growth andguidance (Fig. 1).

DEVELOPING NERVOUSSYSTEM

HB-GAM is abundantly expressed inthe developing nervous system, inwhich its expression peaks aroundone to two weeks postnatally andcontinues to adulthood in somecells (Rauvala et al., 1994). Theoverall pattern of expression, aswell as the in vitro functional re-sults, support a role for HB-GAM asa component of the ECM that regu-lates neuronal cell motility and dif-ferentiation (for review see Bohlenand Kovesdi, 1991; Muramatsu,1994; Rauvala and Peng, 1997).Recombinant, matrix-bound HB-GAM promotes neurite outgrowth,and can act as an axonal guidancefactor in cell culture (Rauvala et al.,1994). Furthermore, HB-GAM lo-calizes to the developing fiber path-ways, as well as to embryonic base-ment membranes, suggesting arole for HB-GAM in the formation ofneuron-target contacts. Indeed,HB-GAM can promote both pre- andpostsynaptic differentiation in theNMJ (Peng et al., 1995; Dai andPeng, 1996). The effect of the neu-ronal agrin isoform on AChR clus-tering in the NMJ was demonstratedto be strongly potentiated by HB-GAM. Thus, it has been proposedthat HB-GAM acts as an integralcomponent of the agrin signalingmechanism (Daggett et al., 1996).

Other TSR domain containingproteins also play an important rolein the development of the nervoussystem. F-spondin and mindin aresecreted adhesion proteins thatshare structural and biochemicalsimilarities (Klar et al., 1992; Hi-gashijima et al., 1997; Umemiya etal., 1997). Expression patterns ofthese molecules overlap in the de-veloping and adult rat cerebral cor-tex, particularly in the pyramidaland granule cells of the hippocam-pus (Feinstein et al., 1999). Bothproteins promote adhesion andoutgrowth of embryonic hippocam-pal and sensory neurons. TSR do-mains of F-spondin have been dem-onstrated to be sufficient topromote neurite outgrowth (Fein-stein et al., 1999). Similarly, TSRdomains of thrombospondin-1 arecritical for neurite outgrowth and

cell attachment effects in hip-pocampal neurons (Osterhout etal., 1992).

However, none of the individualTSR domains are indispensable forthe development of the nervoussystem as indicated by mutantmice studies. Mice lacking HB-GAMare viable, breed normally, andshow no major histological defectsin the nervous system (Amet et al.,2001). Similarly, no apparent mor-phological abnormalities were de-tected in the CNS of midkine knock-out mice (Nakamura et al., 1998),thrombospondin-1 (Lawler et al.,1998) and thrombospondin-2 defi-cient mice (Kyriakides et al., 1998).TSP-1/TSP-2 double knockout micewere recently generated, and dem-onstrated delayed wound healing(Agah et al., 2002); unfortunately,the study did not address regener-ation in the nervous tissue. Modularorganization of the ECM compo-nents may provide the structuralbasis to maintain a high level offunctional redundancy of these pro-teins. Compensation between TSRproteins may thus account for thelack of a pronounced developmen-tal phenotype in mutants withoutparticular TSR-containing mole-cule.

HB-GAM IN THE ADULTBRAIN

In adults, the expression of HB-GAM is limited to certain neuronalsubpopulations, including the pyra-midal neurons of the hippocampus(Wanaka et al., 1993). In additionto this basal level of expression,HB-GAM is induced by stimuli caus-ing neuronal injury or seizures(Wanaka et al., 1993; Takeda etal., 1995). Following ischemia orkainic acid treatment, the expres-sion of HB-GAM is downregulated inneurons (within 48 hr), but inducedin astrocytes four days after the in-jury. On the other hand, rapid (30-min) neuronal induction of HB-GAMmRNA expression has been re-ported in the hippocampal area CA1in response to pentylenetetrazoleinduced seizures (Wanaka et al.,1993), and in the forebrain in re-sponse to tetrahydrocannabinol,the major psychoactive component

16 PAVLOV ET AL.


Figure 1.



of cannabis (Mailleux et al., 1994).Interestingly, two active promotershave been described for HB-GAM inmice (Sato et al., 1997), suggest-ing that two distinct pathways maycontrol HB-GAM expression.

Neuronal expression of HB-GAMmRNA is induced by high-frequencyneuronal activation inducing LTP(Lauri et al., 1996). HFS-inducedexpression of HB-GAM was notcompletely blocked unless antago-nists of both NMDA-receptors andvoltage-gated calcium channelswere used. Therefore, calcium in-flux via both of these routes con-tributes to the regulation of HB-GAM expression (Lauri et al.,1996). The activity-dependent en-hancement in HB-GAM expressionwas the first finding to suggest theinvolvement of endogenous HB-GAM in the regulation of synapticplasticity in the hippocampus.

Application of recombinant HB-GAM into hippocampal slices inhib-its HFS-induced LTP in area CA1,while single-pulse evoked synapticresponses are not affected (Lauri etal., 1998). However, the in vivo role

of HB-GAM in synaptic plasticitywas not determined until recently.Mutant mice studies demonstratedthat HB-GAM transgenic mice thatdisplay a modest overexpression ofthe transgene in the brain have aclearly attenuated LTP, whereasdisruption of the HB-GAM gene en-hances LTP in the CA1 area of thehippocampus (Amet et al., 2001;Pavlov et al., 2002). These resultsstrongly suggest that the endoge-nous HB-GAM acts as an inducibleinhibitor of LTP. Surprisingly, al-though MK displays a striking struc-tural similarity with HB-GAM, it pro-duces much weaker effects on LTP(Ivan Pavlov, Heikki Rauvala, andTomi Taira, unpublished results).

Though significant levels of ex-pression of F-spondin and mindin inrat hippocampus persist duringadulthood, the functional role ofthese proteins in the adult brain re-mains unclear. Both proteins weresuggested to be involved in activ-ity-dependent neural plasticity andremodeling (reviewed by Schererand Salzer, 1996). Modulation of F-spondin binding to the ECM by plas-min supports the possible involve-ment of this protein in activity-dependent processes (Tzarfaty etal., 2001). In addition it has beensuggested that during the activity-dependent synaptic plasticity in thehippocampus, F-spondin acts as atarget for the serine protease, tPA(Tzarfaty et al., 2001). Furtherstudies are warranted to explorethe involvement of other TSR do-main proteins in the regulation ofhippocampal LTP.

MECHANISM OF ACTION

HB-GAM induced neurite outgrowthis mediated by its interaction withthe heparan-sulfate chains of syn-decan-3 (N-syndecan) (Raulo etal., 1994), a transmembrane pro-teoglycan strongly expressed in thedeveloping nervous system and theadult brain (Carey, 1996). Antibod-ies to syndecan-3 inhibit the neu-rite growth of embryonic forebrainneurons on HB-GAM coated matrix(Raulo et al., 1994). The expressionpattern of syndecan-3 correlatesspatiotemporally very well with theexpression of HB-GAM in the ner-

vous system (Nolo et al., 1995).Like HB-GAM, syndecan-3 is ex-pressed in an activity-dependentmanner in hippocampal pyramidalneurons; the expression level of itsmRNA is enhanced after inductionof LTP by HFS (Lauri et al., 1999).Application of soluble syndecan-3blocks HFS-induced LTP (Lauri etal., 1999), while the lack of synde-can-3 in null mutant mice leads tothe enhanced level of LTP resem-bling the phenotype of HB-GAMknockouts (Kaksonen et al., 2002).Remarkably, HB-GAM applicationinto the CA1 area of the hippocam-pus, which strongly attenuates LTPin wild-type mice, had no effect insyndecan-3 knockouts (Kaksonenet al., 2002), thus suggesting thatsyndecan-3 acts as a functional re-ceptor for HB-GAM in the regulationof LTP. However, it is possible thatHB-GAM also interacts with othersyndecans, which are expressed inthe nervous system in a develop-mentally-regulated and region-specific manner. Interestingly, syn-decan-2 is concentrated in thesynaptic junctions at the pre- andpostsynaptic sites (Hsueh et al.,1998). Its expression pattern in-creases in parallel with synapto-physin, suggesting a role in synap-togenesis, in particular at the latestages of synaptic development(Hsueh and Sheng, 1999). Indeed,syndecan-2 was demonstrated toplay a critical role in spine develop-ment, being phosphorylated by theEphB receptor tyrosine kinase(Ethell and Yamaguchi, 1999;Ethell et al., 2001).

Binding of HB-GAM to synde-can-3 results in the phosphoryla-tion of a kinase-active protein com-plex containing the src-familykinases, c-Src and Fyn, and theSrc-substrate, cortactin, in neuro-nal cultures (Kinnunen et al.,1998). Interestingly, assembly ofthis molecular complex is stronglyupregulated following induction ofLTP in the hippocampus, thus sug-gesting involvement of N-synde-can–mediated transmembrane sig-naling in LTP (Lauri et al., 1999).Cortactin in turn regulates actin po-lymerization, which may lead to thestructural changes of the synapticcontact (Uruno et al., 2001).

Figure 1. A: Several ECM proteins con-taining TSR repeats are expressed in theCNS during development and in adulthood.The domain designations are: FS1 andFS2, F-spondin homology 1 and 2; N,thrombospondin N-terminal domain;VWC, von Willebrand factor type A do-main; EGF, epidermal growth factor-likedomain; T3, thrombospondin type III re-peat; C, thrombospondin C-terminal do-main. Rn, Rattus norvegicus; Hs, Homosapiens; Dr, Danio rerio; Mm, Mus muscu-lus. B: Effects of TSR repeats containingECM proteins on neurite outgrowth andhippocampal LTP indicates inhibition ofLTP. C: Effect of recombinant HB-GAM onhigh-frequency stimulation (HFS)-inducedLTP. (a) Pooled data from five experimentsin which LTP was induced by HFS (100 Hz/sec) 10 min after saline (E) or HB-GAM (●)injection. The traces on the right representthe average of three consecutive re-sponses evoked 5 min before and 30 minafter the HFS. (b) Time course of HFS-in-duced LTP following injection of heat-de-natured HB-GAM and amphoterin. Dashedlines show the recordings in which HB-GAMand saline were injected for comparison.All values represent the mean � SEM of atleast five experiments. (c) Dose-depen-dence of HB-GAM induced inhibition of LTP.The values represent the relative increasein synaptic efficacy 30 min following theHFS (Adapted from Lauri et al. 1998).

18 PAVLOV ET AL.


On the other hand, there are sev-eral PDZ domain–containing mole-cules that interact with the intracel-lular domain of syndecan-3 andother syndecans. They are syntenin(Grootjans et al., 1997, 2000),CASK/Lin-2 (Hsueh et al., 1998;Hsueh and Sheng, 1999), syn-bindin (Ethell et al., 2000) and syn-ectin (Gao et al., 2000). All thesemolecules bind to the C-terminalEFYA sequence, fully conservedamong syndecans. Notably, synte-nin was recently shown to interactwith glutamate receptor subunitsGluR1-4 and mGluR7b (Hirbec etal., 2002), raising the possibility

that syndecans are involved in theglutamate receptor targeting, traf-ficking, or recycling.

Another receptor for HB-GAM isPTP�/RPTP� (receptor-like proteintyrosine phosphatase �) (Maedaand Noda, 1996). The interactionbetween HB-GAM and PTP�/RPTP�is important for HB-GAM-inducedneuronal migration (Maeda andNoda, 1998) and morphogenesis ofcell dendrites (Tanaka et al., 2003).PTP�/RPTP� is expressed by thesubsets of neurons and astrocytesin some brain areas, including thehippocampus (Shintani et al.,1998). The electrophysiological

phenotype of the mice deficient inPTP�, which belongs to the samereceptor family as PTP�/RPTP�-4052�, resembles the phenotype ofHB-GAM and syndecan-3 knock-outs, in that these mutants displayenhanced hippocampal LTP (Uetaniet al., 2000). PTP�/RPTP� knockoutmice have been generated re-cently. They did not display anygross morphological abnormalities(Harroch et al., 2000). Yet no dataare available on the putative alter-ations in the mechanisms of synap-tic plasticity in these mutants. How-ever, such alterations are verylikely, since PTP�/RPTP� associateswith sodium channels and affectssodium currents (Ratcliffe et al.,2000). Modulation of phosphataseactivity by HB-GAM may regulateexcitability of the neurons and thuscontribute to the expression onplasticity.

In addition, very recent data indi-cate that HB-GAM might also be in-volved in the regulation of GABAergictransmission in the hippocampus.Mutant mice overexpressing HB-GAM display increased GABAergic in-hibition in the area CA1 of the hip-pocampus (Ivan Pavlov, HeikkiRauvala, and Tomi Taira, unpub-lished observations). Whether thesechanges in GABAergic transmissioncontribute to the behavioral and LTPphenotypes described for these ani-mals is not yet known.

CONCLUDING REMARKS

The functions attributed to the ECMin the nervous system range fromregulation of early developmentand differentiation of neuronal cellsto modulation of activity-depen-dent plasticity in the adult. The TSRdomain–containing proteins, inparticular HB-GAM, are among thebest characterized examples ofECM factors affecting both the de-velopment of neuron-target con-tacts in the developing system, andactivity-dependent synaptic plas-ticity in the adult brain.

Three types of actions for theECM components in synaptic plas-ticity can be proposed (Fig. 2).First, by regulating cellular motilityand morphology, the ECM may con-tribute to structural alterations that

Figure 2. Proposed mechanisms by which activity-dependent changes in the ECM couldaffect neuronal activity and synaptic plasticity (see text of “concluding remarks” fordetails).



are associated with the expressionof synaptic plasticity. Their rolemight be to restrict morphologicalalterations in synaptic plasticity;thus reorganization of the ECM andcell-ECM interactions is required toallow expression of plasticity. Sec-ond, ECM components could coor-dinate transsynaptic signaling dur-ing plasticity. According to thisscheme, ECM ligands would medi-ate signals related to the expres-sion of synaptic plasticity via theircell surface receptors. Third, theECM defines the physical parame-ters of the extracellular space,which regulates diffusion of solublesignaling molecules in the ECS.These mechanisms, overlappingand acting in concert, provide pow-erful means for structural and func-tional regulation of the nervoussystem. Thus, understanding thedynamics of the ECM is importantfor unraveling the neuronal mecha-nisms underlying cognitive pro-cesses, such as learning and mem-ory, as well as the pathologicalmechanisms related to neuronal re-generation and degeneration.

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The role of ECM molecules in activity-dependent synaptic development and plasticity

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