Synaptic adhesion molecules and excitatory synaptic transmission

Synaptic

adhesion

molecules

and

excitatory

synaptic

transmission

Seil

Jang

,

Hyejin

Lee

and

Eunjoon

Kim

Synapticadhesionmoleculeshavebeenextensivelystudiedfor theircontributiontotheregulationofsynapsedevelopment throughtrans-synapticadhesions.However,accumulating evidenceincreasinglyindicatesthatsynapticadhesion moleculesarealsoinvolvedintheregulationofexcitatory synaptictransmissionandplasticity,oftenthroughdirector closeassociationswithexcitatoryneurotransmitterreceptors. Thisreviewsummarizesrecentresultssupportingthis emergingconceptandunderlyingmechanisms,andaddresses itsimplications.

Addresses

1_{CenterforSynapticBrainDysfunctions,InstituteforBasicScience,} Daejeon34141,RepublicofKorea

2_{DepartmentofBiologicalSciences,KoreaAdvancedInstitutefor} ScienceandTechnology,Daejeon34141,RepublicofKorea Correspondingauthor:Kim,Eunjoon(kime@kaist.ac.kr) *

Theseauthorscontributedequallytothework. CurrentOpinioninNeurobiology2017,45:45–50

ThisreviewcomesfromathemedissueonMolecularneuroscience EditedbySusumuTomitaandBrendaBloodgood

ForacompleteoverviewseetheIssueandtheEditorial Availableonline6thApril2017

http://dx.doi.org/10.1016/j.conb.2017.03.005

0959-4388/_ã2017TheAuthors.PublishedbyElsevierLtd.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creative-commons.org/licenses/by-nc-nd/4.0/).

Introduction

Synapticadhesionmoleculesareknowntobeinvolvedin

the regulationof diverse stepsin synapsedevelopment

and maintenance, including theinitial contactbetween

pre-andpostsynapticsidesofsynapses,formationofearly

synapsesand theirdifferentiationintomature synapses,

and maintenanceand plasticity of established synapses

[1–3]. However, recent studies have begun to reveal a

novelroleforadhesionmoleculesinregulatingexcitatory

synaptic transmission and plasticity. Potential

mecha-nisms underlying these functions are often suggested

toincludedirectinteractionorcloseassociationof

adhe-sion moleculeswith neurotransmitter receptors,suchas

NMDA (N-methyl-D-aspartate)and AMPA

(a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate

receptors (NMDARsandAMPARs,respectively).

Synaptic adhesion molecules are thought to cluster

neurotransmitter receptors by interacting with the

cytoplasmicscaffoldingproteinsthatareincomplexwith

neurotransmitter receptors,suchasPSD-95(Figure 1a).

Thistripartiteinteractionmaybesufficientforadhesion

moleculestorecruitneurotransmitterreceptorstositesof

earlytrans-synapticadhesion.Inaddition,itwouldbring

scaffolding protein-associated signaling molecules close

toreceptors.However,synapticadhesionmoleculesmay

also require direct or close cis interactions with

neuro-transmitterreceptors(Figure1b).Forinstance,cis

inter-actionsbetweenadhesionmoleculesand

neurotransmit-terreceptorssituatedonthesamescaffoldingproteinmay

enhancethestabilityoftripartitecomplexesorthe

func-tionalinterplaybetweenthem.

Itshouldbenotedthatexperimentalevidencesupporting

the direct or close interactions of synaptic adhesion

molecules with neurotransmitter receptors is often less

compellingthanthatfortrans-synapticadhesions,likely

because of the weak or transient natureof the

interac-tions.Inthisreview,wefocusonsummarizingresultsthat

arerelatively moreconvincing.

Synaptic

adhesion

molecules

that

regulate

excitatory

synaptic

transmission

and

plasticity

Neuroligin-1

Neuroligin-1,aprototypicalpostsynapticadhesion

mole-cule that interacts with presynaptic neurexins [1], has

been stronglyimplicatedin theregulationof

NMDAR-mediatedsynaptictransmissionandNMDAR-dependent

synaptic plasticity. Supporting datahavebeenobtained

from diverse brain regions, including the hippocampus

[4–10], cortex [11], striatum [12], amygdala [13], and

cerebellum[14].

Neuroligin-1-dependentregulationofNMDARfunction

mayrequireacomplexofPSD-95,anabundantexcitatory

postsynaptic scaffold, with NMDARs and

TARP-con-taining AMPARs. Recent data, however, indicate that

neuroligin-1canalsoassociatewiththeGluN1subunitof

NMDARsthroughextracellularcoupling[4].Inaddition,

theextracellularregionofneuroligin-1cannormalizethe

reduction in NMDAR-mediated synaptic transmission

caused by combined neuroligin-1 knockout (KO) and

neuroligin-3 knockdown(KD) [15].

Notably,neuroligin-1-dependentregulationof

NMDAR-and AMPAR-EPSCs (excitatory postsynaptic currents)

requires a critical residue (E747) in the middle of the

the C-terminal PDZ-binding motif [8]. In addition, an

extracellularregionofneuroligin-1containingthesplice

insertB,knowntoregulateneurexinbinding,isimportant

for neuroligin-1-dependent regulation of

NMDAR-EPSCs and long-term potentiation (LTP) at perforant

path-dentate gyrus (DG) synapses [7], although this

regulation seems to involve a reduction in excitatory

synapsenumberratherthanNMDARcontentat

individ-ualsynapses.

Morerecently,Hevin,asynaptogenicproteinsecretedby

astrocytes,hasbeen shown tointeract withneurexin-1a

and neuroligin-1B (containing splice insert B), a

trans-synaptic pair that does not interact with each other, to

promotepresynapticdifferentiationandpostsynaptic

clus-teringofproteins,includingNMDARs,atthalamocortical

synapses [16]. Because Hevin preferentially recruits

GluN2B-containingNMDARs tosynapses, thereported

extracellular coupling between neuroligin-1 and the

GluN1subunitofNMDARsisunlikelytobecritical[4].

Neuroligin-3andneuroligin-4X

Neuroligin-3, present at both excitatory and inhibitory

synapses[1],enhancesAMPAR-butnot

NMDAR-medi-ated synaptic transmission in a manner requiring E740

(corresponding to E747 in neuroligin-1), whereas

neuroligin-3 enhances inhibitory transmission through

mechanisms that require the presence of neuroligin-2

[8,17].

Neuroligin-3 containing the ASD-related mutation,

R451C, increases AMPAR-mediated synaptic

transmis-sion, slows NMDAR-EPSC decay, increases

GluN2B-containing NMDARs, and enhances

NMDAR-depen-dentLTPinthehippocampus[18].Althoughmolecular

details remain unclear, these apparent gain-of-function

phenotypessuggestthepossibilitythatneuroligin-1

con-taining extracellular mutations can alter AMPAR- and

NMDAR-mediatedsynaptic transmission.

More recently, neuroligin-3 harboring R704C, another

ASD-related mutation, was shown to enhance

neuroli-gin-3 bindingto AMPARsand promote AMPAR

endo-cytosis,whereasthesamemutationintroducedinto

neu-roligin-4Xwasshowntoabolishwild-typeneuroligin-4X–

dependent suppression of AMPAR-mediated

transmis-sion[19].Notably,expressionof wild-type

neuroligin-4Xinthecontextofreducedneuroliginexpression

(miR-mediatedKDof neuroligins-1,-2, and -3)was found to

enhanceAMPARcurrents,anincreasethatwasabolished

by the R704C mutation, which eliminates T707

phos-phorylationbyproteinkinaseC(PKC)[20].

Figure1

(b)

(a) _{Presynapse Presynapse}

Postsynapse Postsynapse Pre-CAM Pre-CAM Post-CAM Post-CAM AMPAR TARP AMPAR TARP NMDAR NMDAR

Scaffolding protein (i.e., PSD-95) Scaffolding protein (i.e., PSD-95) ?

Current Opinion in Neurobiology

Conventionalandemergingviewsonhowsynapticadhesionmoleculesinteractwithneurotransmitterreceptors.

(a)Conventionalview:cytoplasmicscaffoldingproteinssuchasPSD-95,whichinteractwithbothsynapticadhesionmoleculesand neurotransmitterreceptors,mayplayaroleinsynapticcoclusteringofadhesionmoleculesandneurotransmitterreceptors.

(b)Emergingview:synapticadhesionmoleculesandneurotransmitterreceptorsmaydirectlyinteractorcloselyassociatewitheachother,thereby enhancingthestabilityofthecomplexorfacilitatingthefunctionalinterplaybetweenthem.Examplesofsuchfunctionalinterplaycouldinclude regulationoftrans-synapticadhesionsbyligand-boundreceptorsor,conversely,regulationofthepharmacologicalorkineticpropertiesof receptorsbytrans-synapticadhesions

Notably,theinfluenceofneuroligin-3or-4mutationson

AMPAR trafficking and synaptic function appear to be

affected by compensatorychanges during development,

assupportedbytheobservationthatconstitutive

neuroli-gin-3 KO or developmentallyearlyconditional neuroligin-3

KO hasminimaleffectsonAMPARfunctionatcalyxof

Heldsynapses,whereasdevelopmentallylateconditional

neuroligin-3 KO or neuroligin-3 mutations (R451C and

R704C)haveprofoundeffectsonAMPARfunction[21].

Neurexins

Neurexinsarepresynapticadhesionmoleculesthat

inter-act with postsynaptic proteins, including neuroligins,

LRRTMs, and GluD2 [1,2]. Microspheres coated with

neurexin-1bhasbeenshowntorapidlyrecruitNMDARs

andGluA2-containingAMPARslikelythrough

neurexin-neuroligininteractioninanactivity-independentmanner

[22]. In addition, mice lacking neurexin-2a, or both

neurexin-2aand-2b,showreducedexcitatory

presynap-tic release and, intriguingly, reduced postsynaptic

NMDAR function [23], likely through trans-synaptic

neurexin-neuroligin adhesion.

More recently, constitutive inclusion of splice site #4

(SS4)inneurexin-3inmicehasbeenshowntodecrease

postsynapticlevelsofAMPARs,but notNMDARs, and

suppresssynapticAMPARrecruitmentduringLTP[24].

Constitutive removal of SS4 from neurexin-3 by

cre-recombination, however, leads to normalization

AMPAR-mediated synaptic transmission [24]. It is

possible that SS4 in neurexin-3 decreases postsynaptic

AMPAR levels by suppressing the interaction of

neurexin-3 with postsynaptic ligands such as

LRRTMs/neuroligins [2]. These results suggest that

alternativesplicinginneurexinscanregulatepostsynaptic

receptor levelsthroughtrans-synapticadhesion.

LRRTMs

LRRTMs,leucine-richrepeat(LRR)-containing

synap-ticadhesionmoleculesthatinteractwith neurexinsand

PSD-95[2,25,26],havebeenimplicatedintheregulation

ofsynapsedevelopmentaswellassynaptictransmission

andplasticity.Insupportofthesefunctions,double-KD

of LRRTM1 and LRRTM2 suppresses

AMPAR-EPSCs, but not NMDAR-EPSCs, at Schaffer

collat-eral-CA1 synapses [15], whereas LRRTM2 KD

sup-presses NMDAR-EPSCs aswell asAMPAR-EPSCs at

perforantpath-DGsynapses[2].Inaddition,double-KO

of LRRTM1 and LRRTM2 suppresses hippocampal

LTP [27], and LRRTM3 KO in mice decreases the

amplitudeofminiatureEPSCs(mEPSCs)inDGgranule

cells without affecting LTP [28]. Lastly, LRRTM4

interacts with glypicans (presynaptic proteoglycans)

and regulates excitatory synapse density, asevidenced

bythefactthatLRRTM4KO [29]orKD[30]reduces

mEPSC frequencyinDG granulecells;inthe

somato-sensory cortex, LRRTM4 KD suppresses mEPSC

amplitude rather than frequency [30]. Although it

remains largely unclear how LRRTMs regulate

AMPAR/NMDAR-mediated synaptic transmission and

plasticity, it is notable that the reduction in

AMPAR-EPSCs induced by double-KD of LRRTM1 and

LRRTM2isrescuedbyoverexpressionofthe

extracel-lulardomainofLRRTM2[15],suggestingthat

extracel-lularLRRTM2–AMPAR coupling isimportant.

EphBsandephrin-Bs

EphBreceptortyrosinekinases(EphBs),knownto

regu-late dendritic spines, also regulate the trafficking and

functionof NMDARsandAMPARs[31–33].

Ephrin-B-bound EphBs directly interact with NMDARs through

extracellular domains and phosphorylates the GluN2B

subunit of NMDARs at cytoplasmic tyrosine residues

through Srctyrosinekinases, promotingsynaptic

locali-zation of NMDARs and NMDAR-dependent calcium

influxthroughsuppressionofcalcium-dependent

desen-sitization [31,32,34]. EphBs associate with SAP102, a

PSD-95relative knownto regulateNMDARtrafficking

[35], to regulate synapse development through PAK

signaling[36].EphBsalsoregulateNMDAR-dependent

synaptic plasticity through mechanisms involving the

extracellulardomainbut notthetyrosinekinasedomain

[31,32].Clinically,thesurfaceinteractionbetweenEphBs

andNMDARshasbeenassociatedvariousbraindisorders

[31,33],includingencephalitisinvolvingNMDAR

auto-antibodies that weaken the surface interaction [37].

Ephrin-B3, which can be postsynaptically localized for

reversesignaling[32],cis-interactswithEphBsand

inhi-bits EphB-dependent phosphorylation of GluN2B [38].

Ephrin-B3alsodirectlyinteractswithPSD-95ina

phos-phorylation-dependent manner to promote synaptic

localization of PSD-95 [39], an important regulator of

excitatorysynapticstrengthandplasticity[35],andwith

Erk kinases to inhibit postsynaptic mitogen-activated

proteinkinasesignalingand regulateexcitatory synapse

density [40].

N-cadherin

N-cadherin, an Ig domain-containing homophilic

adhesionmoleculeincomplexwithb-catenin,isthought

to stabilize neuronal synapses and regulate excitatory

synaptic transmission and plasticity [2,3].

N-cadherin-dependent regulation ofexcitatory synapticfunction is

supported by the observations that dominant-negative

N-cadherindecreasesmEPSCfrequencyandamplitude

[41], and conditional KO (Camkii-Cre) of N-cadherin

decreases CA1 LTP [42]. Intriguingly, N-cadherin

directly interacts with the extracellular N-terminal

domain of the GluA2 subunit of AMPARs and

sup-presses lateraldiffusion ofGluA2onneuronal cell

sur-faces [43]. In addition, N-cadherin enhances surface

b3integrin

b3integrin,anextracellularmatrixreceptor,islocalized

to postsynaptic sites and regulates AMPAR trafficking

andsynapticplasticity[45].b3integrindirectlyinteracts

withthe GluA2subunitof AMPARsthroughthe

trans-membraneorintracellulardomainsofbothproteins[46].

Theseresults,together withtheabovementioned

extra-cellular coupling betweenN-cadherin and GluA2,

sug-gest the interesting possibility that GluA2 may form a

tripartite complex with N-cadherin and b3 integrin,

althoughthefunctionalconsequencesof thesepotential

interactionsremainunclear.

MDGA2

MDGAs(MAMdomain-containing

glycosylphosphatidy-linositol [GPI] anchors) are Ig domain-containing,

GPI-anchored adhesion molecule known to interact in

ciswithneuroliginsandblockneuroligininteractionswith

neurexins at both excitatory and inhibitory synapses

[47,48,49]. In support of a role for MDGA2 in the

inhibition of AMPAR-mediated synaptic transmission,

a haploinsufficiency of MDGA2 has been shown to

increasemEPSCfrequencyandamplitudeandenhance

AMPAR-EPSCs, without affecting mIPSCs, in

hippo-campalslices[47].

FLRT3

KDof FLRT3(fibronectinleucine-richtransmembrane

protein 3), an LRR-containing postsynaptic adhesion

molecule that interacts with presynaptic latrophilins

[2], decreases mEPSC frequency and amplitude in

dissociated hippocampal neurons, and decreases

AMPAR-EPSCs and NMDAR-EPSCs at perforant

path-DGsynapses[50].ThissuggeststhatFLRT3likely

regulatesbothsynapsedevelopmentandsynaptic

trans-mission,althoughtheunderlyingmechanismisunclear.

IgSF11

IgSF11 (immunoglobulin superfamily member 11) is a

novelIgdomain-containing synapticadhesion molecule

that interacts with PSD-95 and has been implicated in

synapticstabilizationofAMPARs[51].Insupportofthis,

ahigh-throughputsingle-moleculetrackingapproachhas

shownthatKDofIgSF11inculturedneuronsdecreases

mEPSC frequencyandamplitudeand increasessurface

mobilityof theGluA2subunitof AMPARs[51].Igsf11

KO in mice decreases mEPSC amplitude, but not

frequency, in DG granule cells, whereas it suppresses

LTPatSchaffercollateral-CA1synapses.Re-expression

ofIgSF11 inIgSF11-deficient DGgranulecells rescues

mEPSCamplitude,whereasamutantIgSF11lackingthe

C-terminalPDZdomain-bindingmotif partiallyrescues

mEPSCamplitude,suggestingthatboth

PSD-95-depen-dent and -independent mechanisms are involved.

Although, IgSF11 forms a complex with AMPARs in

thebrain,adirectorclosecisinteractionbetweenIgSF11

andAMPARshasnotbeen demonstrated.

SALM1

SALM1 (also known as LRFN2) is a member of the

SALM (synaptic adhesion-like molecule) family of

LRR-containing proteins [52]. Among the five known

SALMs,SALM3and SALM5interact with presynaptic

LAR family receptor tyrosine phosphatases

(LAR-RPTPs) and have strong synaptogenic activities

[53,54], but minimal effects on synaptic strength, as

supported by the decrease in the frequency, but not

amplitude, of mEPSCs in Salm3-KO CA1 pyramidal

neurons [53]. Other SALMs (SALM1, -2, and -5),

however, have been implicated in the regulation of

AMPAR- or NMDAR-mediated synaptic transmission,

as demonstrated by SALM2-dependent synaptic

locali-zation of AMPARs in dissociated hippocampal neurons

[52] and SALM5-dependent promotion of

AMPAR-EPSCs through trans-synaptic interactions with

LAR-RPTPsinhippocampalsliceculture[54].In

addi-tion,SALM1associateswithandinducesdendritic

clus-tering of NMDARs through mechanisms requiring the

C-terminalPDZ-bindingmotifof SALM1, which

inter-actswithPSD-95[52].However,SALM1canalsointeract

with theextracellular and/or transmembranedomain of

the GluN1 subunit of NMDARs in heterologous cells,

indicativeof extracellularcoupling.

NGL-2

Netrin-Gligands(NGLs)areLRR-containingexcitatory

postsynaptic adhesion molecules that interact with

PSD-95 and presynaptic netrin-Gs/LAR-RPTPs. The

netrin-G2 ligand, NGL-2, also known as LRRC4

(leucine-rich-repeat–containing 4) associates with and

induces dendritic clustering of NMDARs and PSD-95,

butnotAMPARs,indissociatedneurons.NGL-2KDor

KOinducesinput-specific decreasesin excitatory

trans-mission,asevidencedbysuppressionofNMDAR-EPSCs

andAMPAR-EPSCsat Schaffercollateral-CA1,but not

TA-CA1, synapses by in utero KD of NGL-2, and by

Schaffer collateral pathway-specific reduction in

excit-atorysynaptictransmissioninLrrc4-KOmice[55].

How-ever, whetherNGL-2 and NMDARs/AMPARs interact

extracellularlyhasnotbeen determined.

Elfn1

Elfn1 (extracellular leucine-rich repeat fibronectin

containing1),anLRR-containingpostsynapticadhesion

moleculeexpressedinsomatostatin-positiveinterneurons

inthehippocampus,localizestoexcitatorysynapsesthat

receive input from hippocampal pyramidal neurons

[56,57].Elfn1isthoughttoregulatepresynapticrelease

through trans-synaptic recruitment of metabotropic

glutamatereceptor7(mGluR7)andGluK1/2-containing

kainitereceptors[56,57].Althoughitisunclearwhether

this trans-synaptic interaction is direct, it clearly

repre-sentsanexampleoftrans-synapticmodulationof

Perspectives

Although evidence implicating synaptic cell adhesion

molecules in the regulation of synaptic transmission

and plasticity through direct or close interactions with

neurotransmitter receptors is accumulating, additional

andstrongerevidenceisrequiredtomakethisemerging

concept more compelling. Such evidence could be

obtainedthroughreal-timeimagingofclose

protein-pro-teininteractionsonthecellsurface,orusingbiochemical

methods, suchas enzymaticbiotinylationofnearby

pro-teins.Inaddition,crystallographicorcryo-electron

micro-scopic analyses of protein-protein complexes could be

attempted. Lastly, functionalconsequences of cis

inter-actions couldbeexplored. For instance, conformational

changesinneurotransmitterreceptorsinducedbyligand

bindingmaymodulatethestrengthorspecificityof

trans-synaptic adhesions, as demonstratedbythe observation

that, upon NT-3 binding, the receptor tyrosine kinase

TrkC associates more strongly with presynaptic PTPs

(a LAR-RPTP)[58,59].Conversely,and perhapsmore

interestingly,synapticadhesions mayregulate the

phar-macologicaland/orkineticpropertiesofneurotransmitter

receptors.

Conflict-of-interest

statement

None.

Acknowledgements

WewouldliketothankHaramParkforthehelpwithfiguredesignand drawing. This work was supported by the Institute for Basic Science (IBS-R002-D1toE.K.).

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