Protein tyrosine phosphatasesPTPd, PTPs, and LAR:presynaptic hubs for synapseorganizationHideto Takahashi1,2 and Ann Marie Craig1

1 Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada V6T 2B52 Institut de Recherches Cliniques de Montre al, Montre al, QC, Canada H2W 1R7

Review

Synapse development requires differentiation of presyn-aptic neurotransmitter release sites and postsynapticreceptive apparatus coordinated by synapse organizingproteins. In addition to the well-characterized neurexins,recent studies identified presynaptic type IIa receptor-type protein tyrosine phosphatases (RPTPs) as media-tors of presynaptic differentiation and triggers of post-synaptic differentiation, thus extending the roles ofRPTPs from axon outgrowth and guidance. Similarlyto neurexins, RPTPs exist in multiple isoforms generatedby alternative splicing that interact in a splice-selectivecode with diverse postsynaptic partners. The parallelRPTP and neurexin hub design facilitates synapse self-assembly through cooperation, pairs presynaptic simi-larity with postsynaptic diversity, and balances excita-tion with inhibition. Upon mutation of individual genesin neuropsychiatric disorders, imbalance of this synapticorganizing network may contribute to impaired cogni-tive function.

IntroductionThe RPTPs are a large protein family with eight subtypesbased on diverse extracellular domains [1,2]. The type IIaRPTPs, composed of three members in vertebrates, leuko-cyte common antigen-related (LAR), PTPs, and PTPd,contain typical cell adhesion immunoglobulin-like (Ig)and fibronectin III (FNIII) domains, suggesting the in-volvement of RPTPs in cell–cell and cell–matrix interac-tions [2–4]. Studies on the roles of RPTPs in the centralnervous system (CNS) had initially focused on axon out-growth, guidance, and regeneration [1,2,4]. More recently,however, many cell biology studies have demonstratednovel roles of RPTPs as presynaptic proteins that trans-synaptically interact with multiple postsynaptic partnersto mediate synaptic adhesion and synapse organization [5–12]. These RPTP-based complexes act in a similar mannerand often in parallel with complexes of presynaptic

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Corresponding authors: Takahashi, H. (Hideto.Takahashi@ircm.qc.ca); Craig, A.M.(acraig@mail.ubc.ca).Keywords: synaptogenesis; neurexin; NGL-3; TrkC; IL1RAPL1; Slitrk.

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neurexins with postsynaptic neuroligins, leucine-richrepeat transmembrane neuronal proteins (LRRTMs), orcerebellin–glutamate receptor-d (GluRd) [13–15]. Further-more, despite a lack of structural homology or commonpostsynaptic binding partners, RPTPs and neurexinsshare a key organizational feature: alternative splicingof each of these presynaptic protein families controls theiraffinity of interaction with multiple postsynaptic bindingpartners. In other words, both RPTPs and neurexins dis-play splice-selective binding codes with diverse postsynap-tic partners. Accumulating evidence indicates that thesetwo parallel synapse organizing pathways cooperate in thedevelopment of many synapses and are linked throughpresynaptic and postsynaptic intracellular pathways. Fur-ther, the genes encoding RPTPs and their postsynapticpartners are associated with neuropsychiatric disordersincluding autism and schizophrenia [16–20], as are likedeleterious mutations in the genes encoding neurexins andpartners [13,21], supporting the possibility that aberrantsynaptic organization might be a fundamental pathogene-sis of neuropsychiatric disorders. We review recent evi-dence for trans-synaptic interaction between presynapticRPTPs and their multiple postsynaptic partners and thefunctions of these complexes in synapse development.Further, we discuss the possible physiological significanceof the apparent hub design of RPTP-based as well asneurexin-based synapse organizing complexes.

Structure of RPTPsLAR, PTPs, and PTPd are encoded by three independentgenes and share overall 66% amino acid identity [22]. Eachcontains extracellular Ig and FNIII domains, modifiedby alternative splicing, which mediate diverse extracellu-lar protein interactions. By contrast, RPTP intracellularprotein interactions are less diverse and involve thetwo intracellular protein tyrosine phosphatase (PTP)domains, the membrane-proximal D1 domain with robustcatalytic activity and the membrane-distal D2 domainwith residual or no catalytic activity [2–4] (Figure 1).RPTPs undergo constitutive proteolytic processing gener-ating an extracellular subunit that remains noncovalentlybound to the phosphatase domain subunit [4], but the

meA meB meC meD

Splicing (PTPσ, PTPδ)

Ig1 Ig2 Ig3 FN1 FN 2 FN3 FN4 FN5 FN6 FN7 FN8

Extracellular Intracellular

Splice site:

LARPTPσPTPδ

N D1 D2

Cataly�cNon-

cataly�c

C

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Figure 1. The structure of type IIa receptor-type protein tyrosine phosphatases (RPTPs). Each RPTP contains three extracellular immunoglobulin (Ig)-like domains followed

by four or eight fibronectin III (FNIII) domains, depending on alternative splicing, and two intracellular protein tyrosine phosphatase (PTP) domains, the membrane-

proximal D1 domain with robust catalytic activity and the membrane-distal D2 domain with residual or no catalytic activity [2–4]. The additional multiple isoforms of RPTPs

are generated by alternative splicing of four mini-exons (meA–meD) encoding short amino acid peptides [22,97]. The meA insert with nine or fewer residues is located in the

second Ig domain (Ig2), presumably affecting the length of a loop region between the D and E b-strands of Ig2, whereas the meB insert with four residues is located at the

end of Ig2 [22,97,98]. The two Drosophila orthologs DLAR and DPTP69D and the single Caenorhabditis elegans ortholog PTP-3 also have two intracellular PTP domains but

differ in the number of extracellular Ig and FNIII domains [2,4,31]. The site of constitutive proteolytic processing that generates an extracellular subunit (E-subunit), which

remains noncovalently bound to the phosphatase domain subunit (P-subunit) [4], is also indicated.

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functional significance of this modification is not clear.RPTPs can also undergo regulated ectodomain sheddingby cleavage at an independent site [23], a mechanism thatmight be used to curtail the synapse organizing activity ofRPTPs.

Hub design of RPTPs: multiple trans-synaptic bindingpartnersRecent studies demonstrate that presynaptic RPTPs maketrans-synaptic adhesion complexes with multiple postsyn-aptic binding partners to regulate synapse organization.These studies first identified many novel postsynapticadhesion molecules that can induce presynaptic differen-tiation in a trans-synaptic manner, here called ‘synapticorganizers’ or ‘synaptogenic’ proteins, through a fibro-blast–neuron co-culture assay [24,25]. In this assay, synap-togenic proteins expressed on the surface of nonneuronalcells trigger formation of functional neurotransmitter re-lease sites in contacting axons of co-cultured neurons.Intriguingly, many of these studies consequently identifiedRPTPs as presynaptic receptors of the synaptogenic pro-teins. The postsynaptic binding partners of RPTPs intrans-synaptic complexes have been identified so far asfollows (Figure 2): netrin-G ligand-3 (NGL-3) [5,6], neuro-trophin receptor tropomyosin-related kinase C (TrkC) [7],interleukin-1-receptor accessory protein-like 1 (IL1RAPL1)[8,9], interleukin-1 receptor accessory protein (IL1RAcP)[10], and Slit and NTRK-like family (Slitrk 1–6) [11,12].

Each synaptic organizer displays an individual code interms of selectivity for RPTP binding (Figure 2). NGL-3binds to LAR, PTPs, and PTPd through their first two FNIIIdomains [5,6]. TrkC binds selectively to PTPs, IL1RAPL1selectively to PTPd, IL1RAcP to LAR, PTPs, and PTPd, andSlitrks selectively to PTPd and PTPs, through the Igdomains of the RPTPs [7–12]. Importantly, alternativesplicing at the meA and meB sites regulates the affinityof interaction of the RPTPs with all of these partners exceptfor NGL-3. Thus, RPTPs may be considered a presynaptichub for coupling to diverse postsynaptic partners.

A similar hub design has emerged for neurexins: dis-tinct presynaptic neurexin isoforms generated from differ-ent genes, alternative promoters, and alternative splicingbind to distinct postsynaptic partners [13–15]. The parallel

design of RPTP and neurexin hubs is striking, very differ-ent in nature from cadherin superfamily interactions inwhich isoform-selective homophilic interactions predomi-nate and contribute to processes such as target recognitionand dendritic self-avoidance [26]. However, control of di-verse extracellular partnerships by splice-selective bind-ing codes appears to be a feature of Ig superfamily proteinsother than RPTPs such as the L1/neuron-glia cell adhesionmolecule (NgCAM) family [27,28], and thus may be a moregeneral mechanism. The possible physiological and path-ological significance of this hub design of RPTPs as well asneurexins is discussed in Box 1.

Functions of RPTPs in synaptic organizationRPTPs in trans-synaptic complexes have three generalfunctions in synaptic organization (Figure 3). One is tomediate cell–cell adhesion at synapses. The second is tomediate presynaptic differentiation, local recruitment ofsynaptic vesicles and release and recycling machinery, aform of retrograde synaptogenic signaling triggered bybinding of the postsynaptic partner to axonal RPTPs.The third is to trigger postsynaptic differentiation, localrecruitment of neurotransmitter receptors, scaffolds, andsignaling proteins, a form of anterograde synaptogenicsignaling triggered by binding of the presynaptic RPTPto dendritic binding partners. A function of postsynapticRPTPs has been also reported [29], and the RPTP com-plexes reviewed here may well participate in regulatingaxon guidance and target specificity [2]. However, thisreview focuses on the functions of RPTPs as presynapticcomponents of synaptic organizing complexes and the asso-ciated retrograde and anterograde signaling pathways.

RPTP functions in synapse organization were first indi-cated by genetic studies in invertebrates. DrosophilaDLAR and Caenorhabditis elegans PTP-3 mutants showaltered presynaptic organization affecting vesicles andactive zones [30,31]. Based on expression patterns andphenotypes of mutant mice [4] as well as recent studiesof RPTP-based complexes as detailed below, PTPs andPTPd may be more important than LAR for synapse orga-nization in vertebrates. In adult brain, LAR shows weakexpression whereas PTPs and PTPd are highly expressed,PTPs very broadly, and PTPd particularly strongly in

523

LAR

NGL-3 TrkC IL1RAPL1 IL1RAcP Slitrk1,2,4-6

PTPσ PTP δ

Presynap�c site

Synap�c cle�

Postsynap�c site

Ig FN III LRRNT/CT LRR PDZ-bindingmo�f

Phosphatasedomain

Tyrosin kinasedomain

TIR

Slitrk2 Slitrk1,4-6

IL1RAcPbIL1RAcP

TrkCTK+

Key:

TrkCTK-

Slitrk3

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Figure 2. The selective binding code of receptor-type protein tyrosine phosphatases (RPTPs) with diverse postsynaptic partners. Individual RPTPs bind to overlapping sets

of postsynaptic partners, as indicated by the lines; broken lines indicate interactions that can occur in vitro but appear to lack physiological relevance. Importantly, except

for netrin-G ligand-3 (NGL-3), these interactions are regulated by alternative splicing of RPTPs at the meA and meB sites. Neurotrophin receptor TrkC can bind all PTPs

forms but insertions at the meA and meB splice sites reduce the apparent interaction [7]. Interleukin-1 receptor accessory protein (IL1RAcP) can bind all forms of PTPd but

insertions at the meA and meB splice sites enhance this interaction [10]. Interleukin-1-receptor accessory protein-like 1 (IL1RAPL1) shows a more complicated selectivity

code, binding best to PTPdA9+B+ and PTPdA6+B+, the two most prevalent forms detected in postnatal day 11 (P11) mouse brain, as well as PTPdA9+B– (+ indicates the

presence of an insert and the number indicates the length) [8].

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scattered cortical neurons, presumptive interneurons, andCA2 hippocampal pyramidal cells [32]. Ptprs�/� andPtprd�/�mice (lacking PTPs or PTPd, respectively) exhibitincreased paired pulse facilitation, enhanced or reducedlong-term potentiation, respectively, and distinct behav-ioral alterations, supporting distinct synaptic functions[33,34]. However, Ptprs�/� hippocampal neurons also ex-hibit an increase in synapse density, probably related toenhanced axon sprouting and/or to a role for postsynapticPTPs [34]. More generally, Ptprs�/� and Ptprd�/�mice alsoexhibit early growth retardation and increased neonatalmortality, and double-mutant mice die at birth due in partto axon targeting defects [33,35–37]. Thus, conditional cell-specific and temporally controlled mutation may be neces-sary to fully dissect the synaptic organizing roles of PTPs

and PTPd in mice in vivo.At least one key downstream effector through which

RPTPs signal intracellularly to organize presynaptic

524

terminals has been identified in invertebrates, liprin-a,a scaffolding protein that binds the D2 domains of allRPTPs [22]. Mutation of the orthologs C. elegans SYD-2and Drosophila Dliprin-a result in synaptic defects similarto, and in cases stronger than, mutation of the RPTPorthologs [30,38]. Additional studies in these systemsfound that liprin-a dimerization and interaction withliprin-b and with the active zone protein ERC (ELKS/Rab6-interacting/CAST) are important for presynapticassembly [39–41]. Binding of liprin-a to the active zoneproteins RIM and CASK, the Rho effector mDiaphanous,and the Arf GTPase-activating protein GIT1 [42] may alsocontribute to presynaptic differentiation. The central roleof liprin-a/SYD-2 in presynaptic differentiation as estab-lished in C. elegans has yet to be tested in mammals,although recent studies demonstrating differential ex-pression and localization of the four a-liprins [43,44]may help fuel further functional studies. RPTP D2

Box 1. Significance of the hub-based design of RPTP and neurexin synapse organizing complexes

Similarly to the neurexin family, the RPTP family regulates synapse

organization through binding to multiple postsynaptic adhesion

partners, with relative affinities regulated by gene identity and

alternative splicing (and for neurexins also by promoter usage). Thus,

RPTPs and neurexins serve as presynaptic hubs (Figure I). This hub-

based design could have physiological and pathophysiological

significance in light of several aspects of synapse development and

function.

(i) Cooperative function: Many individual glutamate synapses con-

tain multiple neurexins and neuroligin and LRRTM partners and

multiple RPTPs and NGL-3, TrkC, ILRAPL1, and Slitrk partners,

suggesting a highly cooperative function in synapse development.

Cooperation may serve to increase both the numbers and diversity

of components recruited to developing synapses. Considering the

network of protein interactions at synapses, many cooperative

actions may be synergistic and not simply additive.

(ii) Synapse self-assembly: As indicated by the co-culture assay,

sufficient local recruitment of either RPTPs or neurexins can

trigger full presynaptic differentiation of functional transmitter

release sites in axons, in a sense utilizing the propensity of

presynapses for self-assembly [99]. This propensity is likely due

in part to a highly interconnected protein interaction network

with multiple cross-links among synaptic components, allowing

for multiple triggers to nucleate synapses.

(iii) Pairing presynaptic similarity with postsynaptic diversity: In

general, synapses share many common presynaptic components

for regulated neurotransmitter release and recycling, but possess

different postsynaptic receptors, scaffolding, and signaling pro-

teins according to chemical type and specific function [100].

Pairing the common neurexin and RPTP presynaptic families with

diverse postsynaptic partners could be a means to orchestrate

this asymmetry in composition and function.

(iv) Balancing excitation and inhibition: Multiple neurexin and PTPd

isoforms interact with excitatory- and inhibitory-specific post-

synaptic partners with differential affinity, regulated by alter-

native splicing, resulting in a mechanism for regulating the

balance of excitation and inhibition, the E/I ratio [101].

(v) Combining circuit stability with synaptic plasticity: In such an

interconnected system where interactions depend on stoi-

chiometry and relative affinities, altering splicing or levels of

one component could alter multiple interactions thus altering

the balance of the whole system, generating plasticity [102].

(vi) Coordinated regulation: Activity and environmentally regu-

lated alternative splicing of neurexins has been reported [103]

and is an ideal way to maintain total levels of neurexins

while altering the balance of interactions with diverse

postsynaptic partners, perhaps mediating coordinated post-

synaptic plasticity. Further coordination could be generated

by shared mechanisms regulating the splicing of RPTPs and

neurexins.

(vii) Specificity of synaptic connections: Although this issue has yet

been poorly addressed experimentally, neurexins and RPTPs

and partners mediate cell–cell adhesion and may control

synaptic partner choice [104,105].

(viii) Adaptation to genetic risk: The highly interconnected and

partially redundant nature of the design, particularly the

utilization of independent neurexin and RPTP hubs, facilitates

maintenance of overall function with loss of individual synapse

organizing proteins. However, the system is susceptible to shifts

in E/I balance and stability/plasticity due to deleterious mutation

of individual genes, shifts that might be corrected by enhancing

or inhibiting the function of remaining proteins. This issue is

clinically relevant given the links of many of these genes to

neuropsychiatric disorders.

NGL-3 TrkC IL1RAPL1 IL1RAcP Slitrk1,2,4,5 NL1(+B) LRRTM1,2 Cbln-GluRδ

(or α –S2)

PTPσ PTP δLAR

Type IIa RPTPs(±meA,B independent, regulates )

β-Neurexins α-Neurexins

Neurexin-1,2,3(-S4 or +S4 or both)

DystroglycanSlitrk3 NL2,3,4,1(-B)

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Figure I. RPTPs and neurexins serve as presynaptic hubs by interacting with diverse postsynaptic partners in an isoform- and splice-selective code. Protein families are

boxed; interactions lacking physiological relevance indicated as broken lines in Figure 2 in main text are not drawn here; postsynaptic partners at inhibitory synapses

are in italics; nonsynaptogenic postsynaptic partners are in gray whereas all others can trigger presynaptic differentiation.

Review Trends in Neurosciences September 2013, Vol. 36, No. 9

domains also bind other potential effectors including Trio,which contains Rho guanine nucleotide exchange factor(GEF) and Rac GEF domains [45], and the actin-bundlingprotein MIM [46].

Whether the tyrosine phosphatase activity of the D1domain is essential for presynaptic differentiation throughRPTPs or more modulatory has not yet been determined.Key substrates of DLAR are the Abl tyrosine kinase andEna, a regulator of actin assembly [2]. Other substrates ofRPTPs that may be important for their synaptic functionsinclude N-cadherin, b-catenin, and p250GAP [29,47,48].The N-cadherin–b-catenin complex stabilizes synaptic con-nections and controls aspects of transmitter release andspine morphogenesis [49]. Because tyrosine phosphoryla-tion of cadherin and catenin suppresses their association,stabilization of the complex by RPTPs may contribute tosynaptic differentiation.

In the anterograde synaptogenic signaling direction, co-culture experiments have shown that RPTPs can trigger

excitatory glutamatergic postsynaptic differentiation [5–8]. This anterograde signaling appears to involve multiplepostsynaptic partners of RPTPs, likely acting in a syner-gistic manner and mediating to some degree distinctaspects of postsynaptic differentiation through differentpathways (Figure 3).

Next, we will review the evidence for molecular inter-actions, cellular functions, and signaling pathways of eachtrans-synaptic complex based on presynaptic RPTPs andtheir specific postsynaptic binding partners.

LAR/PTPs–NGL-3 complexNGL-3 is the first reported synaptic organizer that trans-synaptically interacts with RPTPs [5]. NGL-3 is a memberof the netrin-G ligand (NGL; LRRC4) family [50]. NGL-1and NGL-2 but not NGL-3 selectively bind to the glycopho-sphatidylinositol (GPI)-anchored proteins netrin-G1 andnetrin-G2, respectively, and these isoform-dependentinteractions are involved in input-dependent dendritic

525

LARPTPσ

NGL-3

PSD-95 Tamalin

Liprin-αLiprin-α

PLC-γShc RhoGAP2PSD-95 ? ?

TrkCTK- TrkCTK+ IL1RAPL1 IL1RAcP Slitrk3

PTPσ PTP σ PTP δ

PTPδLARPTPσ PTPδ

Excitatory synapse Inhibitory synapseSynap�c vesicles

Synap�c vesicles

Differen�a�on offunc�onal

presynap�c site

Postsynap�cdifferen�a�on:

Clustering of scaffolds andNT receptors

?

Slitrk1,2,4,5

PTPσ

Glutamate GABA

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Figure 3. The roles of receptor-type protein tyrosine phosphatase (RPTP)-based complexes in synapse development. Multiple RPTP complexes have been identified that

participate in excitatory synapse development, whereas only PTPd–Slitrk3 (Slit and NTRK-like family protein 3) is specific for inhibitory synapses. All of the postsynaptic

partners can trigger local retrograde differentiation of functional presynaptic sites (red arrows) through the conserved intracellular domains of RPTPs, perhaps through

binding liprin-a. RPTP binding to many of the postsynaptic partners can trigger local anterograde recruitment of postsynaptic scaffolds and neurotransmitter (NT) receptors

(green arrows), although it is not known whether this is the case for Slitrk1, 2, 4, and 5, and current evidence suggests that Slitrk3 may not mediate postsynaptic

differentiation. Individual postsynaptic partners can also directly bind and recruit different scaffolding and signaling proteins as indicated.

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segmentation and laminar-specific excitatory synapse de-velopment [50–52]. NGL-3, but not NGL-1 nor NGL-2, bindswith high affinity to LAR, PTPs, and PTPd [5,6]. NGL-3binds to the first two FNIII domains of the RPTPs [6], thus islikely to interact with all RPTP splice variants [5].

In the co-culture assay, NGL-3 induces both excitatoryand inhibitory presynaptic differentiation in contactingaxons, and this activity of NGL-3 is suppressed by additionof soluble LAR ectodomain suggesting that it is mediatedby RPTPs [5]. Unlike the co-culture results, however,neuronal overexpression of NGL-3 promotes excitatory,but not inhibitory, presynaptic differentiation, perhapsdue to localization of NGL-3 in the excitatory postsynapticdensity [5].

Induction-type experiments also indicate that signalingfrom axonal RPTPs to dendritic NGL-3 can induce excitato-ry postsynaptic differentiation. Direct aggregation of recom-binant NGL-3 on the dendrite surface with antibody-coatedbeads results in co-clustering of multiple excitatory, but notinhibitory, postsynaptic components including scaffold pro-teins PSD-95, GKAP, and Shank, AMPA receptors, andNMDA receptors [5]. Notably, the C terminus of NGL-3binds to the first and second PDZ domains of PSD-95 andall MAGUKs [50]. These data suggest that axonal RPTPstrans-synaptically accumulate NGL-3 on the dendrite sur-face and consequently promote excitatory postsynaptic dif-ferentiation through an NGL-3–PSD-95 interaction.

Although NGL-3 can bind to LAR, PTPs, and PTPd invitro [6], additional evidence indicates that its functionalpresynaptic partner is LAR and/or PTPs but not PTPd. Thebinding affinity of NGL-3 to PTPd is much weaker thanthat of another synaptic organizer IL1RAPL1 (describedbelow) to PTPd [8]. Moreover, the presynaptic inducingactivity of NGL-3 in the co-culture assay is comparablebetween wild type neurons and Ptprd�/� neurons [8].Further, mutants of PTPs or LAR but not PTPd containingFNIII but not Ig domains, which can still bind to NGL-3 butnot to other known synaptic partners such as IL1RAPL1,

526

can induce excitatory postsynaptic differentiation [6,8].Thus, NGL-3 acts together with PTPs and/or LAR as abidirectional excitatory synaptic organizing complex.Based on its high expression in brain, we suggest thatPTPs may be the main presynaptic component in thiscomplex.

NGL-3 is widely expressed in the brain [50], thus isunlikely to control input-selective synapse development asdo the other NGL–netrin G complexes. RNAi-mediatedknockdown of NGL-3 reduced excitatory synapse densityin cultured hippocampal neurons [5]. A critical next stepwill be to determine the function of NGL-3 in vivo, whetherit has unique roles and how it acts synergistically withother synapse organizing complexes.

PTPs–TrkC complexThe neurotrophin receptor tropomyosin-related kinase(Trk) family is well characterized for its roles in neuronaldifferentiation, survival, and maintenance through neuro-trophin-dependent activation of tyrosine kinase signaling[53,54]. By contrast, it had been predicted that Trks mayalso have cell adhesion functions given their extracellulardomain structures composed of leucine-rich repeat (LRR)and Ig domains [53,54]. Recently, an unbiased expressionscreen based on the co-culture assay isolated a TrkC non-catalytic isoform as a synaptic organizer [7]. A candidatecell surface binding screen using TrkC ectodomain proteinsthen isolated PTPs as a TrkC binding partner. Despiteconsiderable homology, neither TrkA nor TrkB can inducepresynaptic differentiation in co-cultured hippocampal orcortical neurons nor bind to RPTPs [7].

In the co-culture assay, both TrkC noncatalytic(TrkCTK–) and catalytic (TrkCTK+) isoforms induce excit-atory, but not inhibitory, presynaptic differentiation withalmost equal activity [7]. The synaptogenic region of TrkCbinds to PTPs but not PTPd or LAR (at least not to thesplice forms that were tested), and this interaction isregulated by alternative splicing with insertions at the

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meA and meB splice sites of PTPs reducing the observedbinding [7]. Presynaptic differentiation by TrkC ectodo-main-coated beads is abolished by axonal expression ofa PTPs mutant lacking the intracellular region(PTPsDICD), and forced accumulation of PTPs, but notPTPsDICD, on the axon surface is sufficient to inducepresynaptic differentiation [7]. This evidence supportsthe idea that axonal PTPs mediates presynaptic inductionby dendritic TrkC and that signal transduction by theintracellular domain of PTPs is required.

Trans-synaptic interaction between axonal PTPs anddendritic TrkC also generates an anterograde synapto-genic signal for excitatory postsynaptic differentiation[7]. Although TrkCTK– and TrkCTK+ lack typical PDZdomain-binding motifs, direct surface aggregation ofTrkCTK– or TrkCTK+ on dendrites is sufficient to induceco-aggregation of PSD-95 and NMDA receptors [7]. Inaddition, TrkCTK– can bind the postsynaptic scaffold pro-tein tamalin to activate Arf6–Rac signaling [55] andTrkCTK+ can bind and activate phospholipase Cg, Shc,and Frs2 leading to Ras and PI3 kinase [54], criticalregulators of excitatory synaptic plasticity. These interac-tions might be involved in TrkC-mediated excitatory post-synaptic signaling and contribute to the diversity ofexcitatory postsynaptic composition.

Independent loss-of-function experiments utilizing aTrkC neutralizing antibody that inhibits TrkC–PTPs

interaction or RNAi-mediated knockdown of TrkC sup-port the involvement of the TrkC–PTPs interaction inexcitatory synapse development [7]. Notably, the TrkCneutralizing antibody completely blocks presynaptic in-duction by TrkC but only partially blocks postsynapticinduction by PTPs [7], consistent with alternative anter-ograde pathways from PTPs such as through NGL-3.TrkC catalytic and noncatalytic isoforms are expressedwidely in the postnatal and mature brain [56,57] andlocalize to excitatory postsynaptic sites [7]. Transgenicoverexpression of TrkC results in elevated levels ofNMDA receptors and enhanced and longer-lasting long-term potentiation in hippocampus [58], supporting a roleof TrkC in excitatory synapse function. However, consid-ering the pleiotropic roles of TrkC in nervous systemdevelopment and the perinatal lethal phenotype ofNtrk3�/� mice lacking TrkC [59], more selective manip-ulations will be necessary to test the specific functions ofthe TrkC–PTPs synaptic complex in vivo. The TrkCknockdown phenotypes on synaptic markers in cultureand spine density in vivo are fully rescued by RNAi-resistant TrkCTK– [7], indicating that the synapse orga-nizing function of TrkC does not require kinase activity.However, the intriguing possibilities remain that TrkC–PTPs trans-interaction may affect the activity of TrkCtyrosine kinase and/or PTPs phosphatase to regulateexcitatory synapse development and/or plasticity.

PTPd–IL1RAPL1 and PTPd/PTPs/LAR–IL1RAcPcomplexesIL1RAPL1 and IL1RAcP belong to the interleukin-1/Tollreceptor family, possess Ig-like domains extracellularlyand a Toll/IL1R (TIR) domain intracellularly, and sharesequence homology [60]. The human gene encoding

IL1RAPL1 has been well characterized to be associatedwith cognitive diseases ranging from nonsyndromic X-linked mental retardation to autism [18,61]. Two indepen-dent studies recently revealed that trans-synaptic interac-tion between postsynaptic IL1RAPL1 and presynapticPTPd bidirectionally regulates excitatory synapse devel-opment [8,9]. The IL1RAPL1 extracellular region selec-tively binds to PTPd but not LAR or PTPs [8,9].Furthermore, the IL1RAPL1 extracellular region is suffi-cient for inducing excitatory presynaptic differentiation inthe co-culture assay, and this activity is abolished in co-cultures with Ptprd�/� neurons [8].

Neuronal overexpression of IL1RAPL1 not onlyenhances excitatory presynaptic inputs but also increasesdendritic spine formation and clustering of excitatorypostsynaptic proteins such as PSD-95 and Shank2[8,9,62]. Intracellularly, the IL1RAPL1 TIR domain bindsto RhoGAP2, a GTPase-activating protein that inhibitsRac1 activity and regulates dendritic spine number andmorphology, and neuronal overexpression of IL1RAPL1recruits RhoGAP2 to synapses [9]. The IL1RAPL1 C-ter-minal domain binds to PSD-95 via a noncanonical PDZbinding motif [62]. IL1RAPL1 also activates the JNKpathway and consequently phosphorylates PSD-95 thusregulating synaptic accumulation of PSD-95 [62,63]. Con-sistent with these molecular pathways, spine induction byIL1RAPL1 requires its TIR domain, whereas Shank2 clus-tering requires both the TIR and C-terminal domains [8].Interestingly, postsynaptic protein recruitment and spineinduction by IL1RAPL1 require trans-synaptic interactionwith PTPd [8,9]. This finding may reflect a simple require-ment for PTPd binding to localize IL1RAPL1 to excitatorypostsynaptic sites. However, it has not been definitivelyshown whether dendritic recruitment of IL1RAPL1 by PTPd

is sufficient to recruit postsynaptic proteins, for example, bydirect aggregation of IL1RAPL1 on dendrites as describedabove for NGL-3 and TrkC, but this probability is supportedby the finding that soluble IL1RAPL1 ectodomain inhibitspostsynaptic differentiation by PTPd [8].

Proteins related to IL1RAPL1 also function in excitato-ry synapse organization. IL1RAPL2 induces presynapticdifferentiation in the co-culture assay, although with lesspotency than IL1RAPL1, and when overexpressed in neu-rons IL1RAPL2 also increases excitatory presynapticinputs and dendritic spine density [9,10]. Other membersof the IL1 receptor and accessory protein families do nothave synaptogenic activity with one important exception,IL1RAcP [10]. Postsynaptic IL1RAcP and presynapticPTPd also function as a bidirectional excitatory synapticorganizing complex [10]. IL1RAcP functions as a co-recep-tor with interleukin-1 receptor type I (IL1RI) for mediatingimmune and inflammatory responses to IL1 family cyto-kines [60], unlike IL1RAPL1 which lacks such function.Thus, reminiscent of TrkC, IL1RAcP appears to serve twodistinct functions, one with IL1 and IL1R1 in immuneregulation and inflammation and another with PTPd insynaptic adhesion and synapse organization.

An elegant series of co-culture, ectodomain-bead induc-tion, IL1RAcP neuronal overexpression and RNAi knock-down, recombinant protein interaction, cell surface binding,and cell aggregation assays were used to demonstrate a

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role for IL1RAcP–PTPd in excitatory synaptic adhesion andpresynaptic and postsynaptic differentiation in culturedneurons [10]. IL1RAcP exists in two isoforms as the morewidely expressed IL1RAcP and the CNS-specific IL1RAcPb[64]. IL1RAcPb terminates in a consensus type II PDZdomain binding sequence. Both isoforms of IL1RAcP caninduce excitatory presynaptic differentiation using theirextracellular regions, but only IL1RAcPb can also promotedendritic spine formation [10]. IL1RAcP-induced presynap-tic induction is significantly but partially abolished in co-cultures with Ptprd�/� neurons, indicating that the weakerinteraction observed between IL1RAcP and PTPs and LARmay also be functionally important [10]. Likewise, PTPd-induced postsynaptic induction is significantly but partiallyabolished in co-cultures with IL1RAcP�/� neurons [10],indicating that IL1RAcP is one of multiple functional post-synaptic partners for PTPd.

In vivo knockout data confirm roles for IL1RAPL1 andIL1RAcP in excitatory synapse development. IL1RAPL1�/� mice exhibit deficits in excitatory synapses, reducedasymmetric synapse density, and reduced spine densityin hippocampal CA1 stratum radiatum [62]. Long-termpotentiation was reduced when elicited by theta burststimulation but not by high frequency stimulation, thusshowing stimulus-dependent effects [62]. Basal transmis-sion assessed by input–output response, minimal stimula-tion failure rate, and miniature excitatory postsynapticcurrent (mEPSC) frequency was not significantly im-paired. Curiously, mEPSC frequency was substantiallyreduced in IL1RAPL1�/� hippocampal neurons co-culturedwith wild type neurons [62], perhaps reflecting a competi-tive effect dependent on transcellular differences inIL1RAPL1 level as recently found for neuroligin-1 [65].Reductions in phosphorylation of JNK and of PSD-95 werealso found in IL1RAPL1�/� neurons [62], consistent withthe molecular pathways described above. WhetherIL1RAPL1 functions exclusively at excitatory postsynapticsites is not yet clear because differences were observed insynaptic transmission within cerebellar GABAergic net-works in IL1RAPL1�/�mice [66] and evidence from zebra-fish supports direct presynaptic functions of IL1RAPL1[67]. Synaptic phenotypes of IL1RAcP�/� mice have notbeen extensively studied but a significant reduction inspine density also confirms a role in excitatory synapsedevelopment in vivo [10].

A major finding from these recent studies on IL1RAPL1and IL1RAcP as well as TrkC is the revelation of distinctcodes for RPTP binding regulated by alternative splicingof RPTPs [7,8,10] (Figure 2). Perhaps related to differ-ences between IL1RAPL1 and IL1RAcP in their RPTPbinding codes is the finding that in the co-culture assay,IL1RAPL1 induces only excitatory presynaptic differenti-ation whereas IL1RAcP induces not only excitatory butalso some inhibitory presynaptic differentiation [8,10].Taken together with additional studies on TrkC andSlitrks (see below), these differences raise the intriguingpossibility that glutamatergic and GABAergic axonsmay have differential expression patterns of RPTP familymembers and splice forms. Neuron type-specific expres-sion and splicing of RPTP variants remains to beaddressed experimentally.

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PTPd/PTPs–Slitrk1–6 complexesThe Slitrk family consists of six brain-specific transmem-brane proteins (Slitrk 1–6) that possess extracellular LRRdomains homologous to the axon guidance molecule Slitand intracellular C-terminal tyrosine residues with sur-rounding sequences homologous to the Trk family [68]. Allmembers of the Slitrk family induce presynaptic differen-tiation in the co-culture assay [11,69]. Intriguingly, Slitrk3can induce inhibitory, but not excitatory, presynaptic dif-ferentiation whereas other family members induce bothexcitatory and inhibitory presynapses [11]. Similarly, uponoverexpression or knockdown in neurons, Slitrk3 selec-tively affects GABAergic inputs whereas any of Slitrk1,Slitrk2, Slitrk4, or Slitrk5 affect glutamatergic inputs, andrecombinant protein localization for Slitrk1–3 supportsthese selective phenotypes [11,12].

All Slitrks can interact with PTPd [11] and Slitrk1–3 atleast can also interact with PTPs [12]. RNAi-mediatedknockdown of selective RPTPs in neurons co-cultured withSlitrk-expressing cells suggests that PTPs mediates theexcitatory presynaptic differentiation induced by Slitrks,particularly Slitrk1 and Slitrk2 [12]. Curiously, PTPd,shown above to function with IL1RAPL1 and IL1RAcPin excitatory synapse development, mediates the inhibito-ry presynaptic differentiation induced by Slitrks, particu-larly Slitrk3 [11,12]. Thus, it is puzzling how Slitrk3–PTPd

can function selectively in inhibitory synaptic organizationand IL1RAPL1/IL1RacP–PTPd in excitatory synaptic or-ganization. The PTPd isoform that contains full meA andmeB inserts, a major isoform of PTPd in the brain [8], canbind to all Slitrks including Slitrk3 [11], IL1RAPL1 [8], andIL1RacP [10], although perhaps with different affinity.Given that the meA and meB splice inserts of PTPd differ-entially control its binding to IL1RAPL1 and IL1RAcP[8,10], it is possible that differential splicing of PTPd inGABAergic versus glutamatergic axons contributes to se-lectivity in partner binding and function. Such a mecha-nism would be similar to the role of splicing at the S4 site inneurexins, which along with a/b promoter usage controlstheir binding to different neuroligins, LRRTM1/2 and cer-ebellin–GluRd [14,15]. However, more complicated mech-anisms involving axon-selective co-receptors orsuppressors to regulate specificity of interactions cannotbe ruled out.

Whereas most of the other RPTP complexes have dem-onstrated bidirectional synaptic organizing activities, theSlitrk–PTPd/PTPs interaction has only been shown toinduce presynaptic differentiation. A PTPd isoform thatcontains full meA and meB inserts and can bind to allSlitrks [11] induces only excitatory not inhibitory postsyn-aptic protein clustering in co-culture assays [8], suggestingthat Slitrk3 may need to cooperate with other synaptogeniccomplexes such as neurexin–neuroligin-2 for inhibitorysynapse development. It remains an open question wheth-er any of the RPTP–Slitrk complexes can directly mediatepostsynaptic differentiation.

Slitrks 1–5 are widely expressed in distinct but over-lapping patterns in the brain, whereas Slitrk6 is largelyrestricted to the thalamus, cerebellum, medulla, and is alsounique in its high expression in many nonneural tissues[68,70]. Only Slitrk3 and Slitrk5 have been extensively

Table 1. Association of RPTPs and postsynaptic partners with neuropsychiatric disorders

Proteina Gene Locus Mutation Phenotype Refs

PTPd PTPRD 9p23–p24.3 �Two SNPs in 50UTR Restless legs syndrome [16,106]

�Four CNVs (hemizygous deletion) ADHD [107]

�de novo CNV (deletion) ASD [17]

�de novo CNV (duplication) Bipolar disorder [108]

PTPs PTPRS 9p13.3 �de novo CNV (deletion, multigenic) ASD [17]

IL1RAPL1 IL1RAPL1 Xp22.1–p21.3 �Deletions

�Nonsense mutations (Y459X, W487X)

Mental retardation [61,109–114]

�de novo frameshift mutation (I367SfsX6)

�Deletions

ASD [18,115]

�CNV (duplication) Schizophrenia [19]

Slitrk1 SLITRK1 13q31.1 �Frameshift mutation (L422fs)

�30UTR mutation

Gilles de la Tourette’s syndrome [116,117]

�Two missense mutations (R584K, S593G) Trichotillomania [118]

Slitrk2 SLITRK2 Xq27.3 �Rare missense mutation (V89M) Schizophrenia [115]

Slitrk3 SLITRK3 3q26.1 �Altered expression of miRNAs against Slitrk3 mRNA Autism [119]

Slitrk6 SLITRK6 13q31.1 �CNV (deletion) Epilepsy [120]

TrkC NTRK3 15q25.3 �Interstitial duplication of 15q24-26

�SNP in 50UTR

�SNP in 30UTR

Panic disorder [121–123]

�SNPs in 30UTR (two SNPs at miRNA target site) OCD [123,124]

�Five SNPs (intron) Major depression [125]

�Three SNPs (intron) Schizophrenia [126]

aFor LAR encoded by the PTPRF gene at locus 1p34.2, we are not aware of mutations associated with neuropsychiatric disorders.

Review Trends in Neurosciences September 2013, Vol. 36, No. 9

studied with respect to synaptic phenotypes in vivo.Slitrk5�/� mice show reduced levels of AMPA and NMDAreceptors in striatum and reduced corticostriatal transmis-sion [71] supporting a role in excitatory synapse develop-ment in striatal neurons. Considering the neuron cultureand RPTP binding experiments described above, it is likelythat Slitrk5 contributes to excitatory synapse developmentthrough interaction with PTPs. Slitrk5�/� mice exhibitexcessive self-grooming [71] and may serve as a modelfor obsessive compulsive disorder (OCD) (Table 1).

Slitrk3�/� mice exhibit decreases in GABAergic but notglutamatergic presynaptic markers and decreases in mini-ature inhibitory postsynaptic current (mIPSC) frequencywith no effects on mEPSCs in the hippocampal CA1 region[11]. These data support the cell culture studies, indicatingthat Slitrk3 mediates functional inhibitory synapse devel-opment in vivo, presumably through its interaction withPTPd. Slitrk3�/� mice also show increased seizure suscep-tibility and occasional spontaneous seizures, suggesting awidespread impairment of inhibitory synapses [11]. Curi-ously, within the CA1 region most intensively analyzed,inhibitory terminals in the center of stratum pyramidalewere lost whereas those at the edges of stratum pyramidalewere spared in Slitrk3�/� mice [11]. This finding mayrelate to the distinct physiological properties of pyramidalcells residing at different sublayers within stratum pyr-amidale [72] and presents an interesting cell biologicalpuzzle, perhaps reflecting a selective role of Slitrk3–PTPd

at synapses made by specific classes of basket cells and/oraxo-axonic cells. In hippocampal CA1 stratum pyramidale,by immunofluorescence Slitrk3�/� mice show impairedinhibitory presynaptic differentiation ([11]; potentialeffects on postsynaptic differentiation are not yet known),whereas mice lacking neuroligin-2 show impaired inhibitorypostsynaptic differentiation with almost normal inhibitorypresynaptic differentiation [73]. Thus, Slitrk3–PTPd and

neuroligin-2–neurexin pathways may cooperatively controlinhibitory synapse development by mainly bearing trans-synaptic retrograde and anterograde signals, respectively.

Cooperative mechanisms among RPTP-based andneurexin-based synapse organizing complexesOverall, the physical and functional trans-interactions ofRPTPs as well as neurexins with their multiple postsyn-aptic binding partners generate a complicated molecularnetwork. Many of these complexes have fairly widespreadoverlapping expression patterns, consistent with cooper-ative functions. For example, evidence for function atglutamatergic synapses in hippocampal cultures hasbeen published for RPTPs with NGL-3 [5], TrkC [7],IL1RAPL1 [8], Slitrk1, Slitrk2, Slitrk4, and Slitrk5[12], and for neurexins with neuroligin-1, neuroligin-3[74,75], LRRTM1, and LRRTM2 [69,76–78], and abouthalf of these complexes have verified roles at synapsesfrom hippocampal CA3 to CA1 stratum radiatum in vivo.As discussed above, PTPd–Slitrk3 and neurexin–neuro-ligin-2 also function together at hippocampal GABAergicsynapses, particularly onto pyramidal cell somata. Thus,it appears that multiple RPTP-based and neurexin-basedcomplexes act in parallel to coordinate the organization ofindividual synapses.

Within the RPTP-based system, the hub design promotescooperation among complexes with multiple postsynapticpartners, but also competition among postsynaptic partnersthat bind to individual RPTP isoforms if their amounts arelimiting (and similarly within the neurexin-based system).Implications of this hub design are further discussed in Box1. Within the RPTP-based system, there is also the potentialfor more direct cooperative interactions by simultaneousbinding of multiple postsynaptic partners to an individualRPTP (Figure 4A). Such triple complexes may have en-hanced stability and serve to recruit multiple postsynaptic

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NGL-3

TrkC

PTPσ(A) (C)

LARPTPσPTPδ

Neurexin

ELKS

Liprin-α

CASKSyd-1

Neurexin

(B)

PDZ1 PDZ2 PDZ3 SH3 GK

PSD-95

Neu

rolig

in-1

NGL

-3

IL1R

APL1

LAR/PTP σ

PTPδ Neurexin

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Figure 4. Cooperative mechanisms among receptor-type protein tyrosine phosphatase (RPTP)-based and neurexin-based synapse organizing complexes. (A) Netrin-G

ligand-3 (NGL-3) and the neurotrophin receptor TrkC bind to distinct domains of PTPs [the first two fibronectin III (FNIII) domains for NGL-3 [6] and the Ig domains for TrkC

[7]]. Therefore, NGL-3 and TrkC could cooperatively regulate excitatory synapse organization through possible simultaneous binding to PTPs. Although domain mapping

has not been reported for the other RPTP partners, their regulation by meA and meB splicing suggests that interleukin-1-receptor accessory protein-like 1 (IL1RAPL1) and

interleukin-1 receptor accessory protein (IL1RAcP) also bind to the Ig domains. Thus, NGL-3, which can bind to all RPTPs, might be rather unique in simultaneously binding

to RPTPs along with a variety of other postsynaptic partners. (B) NGL-3 and IL1RAPL1 can each bind to the first two PDZ domains of PSD-95 [50,62], and neuroligins bind to

the third PDZ domain of PSD-95 ([127]). Leucine-rich repeat transmembrane proteins (LRRTMs) also bind PSD-95 [69], Thus, scaffolding by PSD-95, which itself forms head-

to-head multimers, and other members of the MAGUK family, may stabilize many of these trans-synaptic complexes and function to transduce the anterograde synapse

organizing signal by recruiting postsynaptic receptors, other scaffolds, and signaling proteins. (C) The most direct known link from RPTPs to neurexins is through liprin-a

binding to CASK, which in turn binds to neurexins [128]. However, cultured cortical neurons lacking CASK exhibit normal evoked glutamatergic and GABAergic

transmission [129] and Caenorhabditis elegans liprin-a and CASK orthologs Syd-2 and Lin-2 do not colocalize or genetically interact [39], raising questions about the

importance of this link. Another key pathway recently identified in Drosophila [130] links the neurexin DNrx-1 to the liprin-a DSyd-2 through DSyd-1, a Rho GTPase-

activating protein that contains PDZ and C2 domains initially identified from a C. elegans screen for genes contributing to synapse development [131]. It is not yet clear

whether Syd-1 directly binds liprin-a or whether they interact through simultaneous binding to ERC [132].

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components. Within the presynaptic terminal, intracellularinteractions so far appear to be conserved among RPTPs(e.g., all interact with liprin-a), so each RPTP complex maycontribute in an additive rather than unique manner. How-ever, individual RPTP postsynaptic partners can recruitunique interacting proteins contributing to the diversityof postsynaptic specializations. Cooperative interactionsmay also occur within the postsynaptic density, and mayextend to neurexin partners as well, by joint binding toscaffold proteins such as PSD-95 (Figure 4B). Thus, scaf-folding by PSD-95, which itself forms head-to-head multi-mers, and other members of the MAGUK family, maystabilize many of these trans-synaptic complexes and func-tion to transduce the anterograde synapse organizing signalby recruiting NMDA receptors, stargazin, and AMPA recep-tors, other scaffolds such as GKAP/SAPAP, and signalingproteins such as SynGAP [79].

Although individual RPTP or neurexin trans-synapticpartners are sufficient to induce presynaptic differentia-tion in co-culture, it is likely that these multiple systemscooperate for bona fide presynaptic differentiation be-tween neurons. Interestingly, PTPs as well as neurexinsfunction as receptors for a-latrotoxin, which triggers mas-sive neurotransmitter release [80,81], suggesting sharedpresynaptic signaling pathways in neurotransmitter re-lease. Based on current limited knowledge about themechanisms of retrograde synaptogenic signal transduc-tion for the RPTP and neurexin pathways, two majorroutes of convergence within presynaptic terminals areapparent (Figure 4C), both through liprin-a, which isthought to be a core scaffold protein that governs presyn-aptic differentiation through RPTPs. It will be importantto assess the role of convergent signaling between RPTPand neurexin pathways in presynaptic differentiation andthe specific roles of liprin-a, CASK, ERC, and Syd-1 inmammalian systems.

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Possible modulatory mechanisms regulating RPTP-based synaptic organizing complexesPrevious studies have identified additional secreted orextracellular matrix molecules that can bind to the ex-tracellular domains of RPTPs or their trans-synapticbinding partners, raising intriguing possibilities formodulation of the synaptic organizing activity of thesecomplexes (Figure 5). Chondroitin sulfate proteoglycans(CSPGs) and heparan sulfate proteoglycans (HSPGs)bind to RPTPs [82,83]. HSPGs regulate DLAR functionin synapse development at the Drosophila neuromuscu-lar junction [84], and several studies demonstrate theinvolvement of extracellular matrix in synapse formationand/or plasticity in mammalian neurons [85]. Thus, theseextracellular matrix molecules might enhance or sup-press the synaptogenic activity of RPTP-based synapticorganizing complexes to regulate synapse developmentand/or plasticity (Figure 5A).

Other interactions specific to individual RPTP bindingpartners may also modulate the function of individualcomplexes. The isolation of TrkC as a synaptogenic pro-tein was surprising given its well-known role as a neu-rotrophin receptor. TrkC binds via different domains toneurotrophin-3 and PTPs [7,54,86], raising the possibil-ity for cross-modulation. Some of the effects of neurotro-phin-3 on synaptic efficacy [87,88] may be throughmodulating the synapse organizing activity of theTrkC–PTPs complex by its dimerization and/or internal-ization (Figure 5B). Considering further evidence thatneurotrophin-3 undergoes activity-dependent release[89], neurotrophin-3 modulation could represent a wayto regulate the TrkC–PTPs complex by synaptic activity.

Another potential form of modulation specific toIL1RAcP is modulation by the cytokine IL1. In the immunesystem, IL1RAcP forms a heterodimer with IL1RI to form asignaling-competent complex for binding and transducing

TrkC

NT-3

PTPσ PTP σ

(A) (B) (C)

CSPGHSPG

TrkCIL1RAPL1IL1RAcPSlitrks

PTPσ, PTP δ, LAR

or++or++or++

IL1RAcP

IL1

IL1RI

PTPδ

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Figure 5. Potential modulatory mechanisms regulating receptor-type protein tyrosine phosphatase (RPTP)-based synapse organizing complexes. (A) Chondroitin sulfate

proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPGs) bind via their glycosaminoglycan chains to the first immunoglobulin-like domain of leukocyte common

antigen-related (LAR), PTPs, and PTPd [82,83]. CSPGs and HSPGs compete for binding to RPTPs and have opposing PTPs-dependent effects on neurite outgrowth of dorsal

root ganglion neurons, perhaps through differential effects on RPTP oligomerization [133]. The extracellular matrix laminin–nidogen complex also binds to the fifth

fibronectin III (FNIII) domain of LAR in a splice-selective manner, only to LAR isoforms lacking an insert at the meC site [134]. These extracellular matrix molecules might

modulate the synaptogenic activity of RPTP-based synaptic organizing complexes. (B) The neurotrophin receptor TrkC requires only its second Ig domain to recognize

neurotrophin-3 (NT-3) [54,86], whereas only its leucine-rich repeat (LRR) plus first Ig domains are needed to bind PTPs and trigger synaptogenic signaling [7]. Thus, TrkC

could potentially simultaneously bind neurotrophin-3 and PTPs, raising the possibility for cross-modulation. In general, neurotrophin-3 binding to TrkC induces its

dimerization, activation of the kinase, kinase-dependent recruitment of signaling intermediates, and internalization of TrkC [54]. Further, neurotrophin-3 treatment enhances

excitatory synaptic transmission and alters synaptic plasticity [87,88]. Some of these effects of neurotrophin-3 may be through modulating the synapse organizing activity

of the TrkC–PTPs complex. (C) In the immune system, interleukin-1 receptor accessory protein (IL1RAcP) forms a heterodimer with the type I interleukin-1 receptor (IL1RI) to

form a signaling-competent complex for binding and transducing the effects of IL1 [60]. There is evidence for neuronal expression of IL1R1 [135] and IL1 has rapid effects on

NMDA receptor-mediated transmission and synaptic plasticity [136], although whether IL1R1 localizes with IL1RAcP to postsynaptic sites has not been reported. If so, IL1

through IL1RI might modulate the synapse organizing activity of IL1RAcP by altering the binding of IL1RAcP to PTPd.

Review Trends in Neurosciences September 2013, Vol. 36, No. 9

the effects of IL1 [60]. If such a heterodimer forms ondendrites, IL1 through IL1RI might modulate the synapseorganizing activity of IL1RAcP (Figure 5C). Given that IL1is a proinflammatory cytokine, such a modulatory mecha-nism could be important for regulating synaptic functionin neuroinflammatory conditions including stroke andbrain injury.

Disease association of RPTP and their binding partnersSeveral neuropsychiatric disorders such as autism spec-trum disorders (ASD), schizophrenia, OCD, and atten-tion deficient hyperactivity disorder (ADHD) are highlyheritable, motivating large-scale genetic studies forthese disorders. Genome-wide single nucleotide polymor-phism (SNP) association, copy number variant (CNV)identification, and whole-exome sequencing have uncov-ered many gene mutations associated with these disor-ders. A subset of these mutations target genes involvedin development and function of synapses. In addition tomutations in genes encoding neurexins and partnersneuroligins, LRRTMs, and cerebellin–GluRd [13,21,90–93], mutations in genes encoding PTPd, PTPs, and RPTPpostsynaptic binding partners IL1RAPL1, the Slitrkfamily, and TrkC have been identified in individualswith neuropsychiatric disorders, as summarized inTable 1.

Generally, mutations in a single gene encoding a syn-aptic organizer are associated with a range of neuropsy-chiatric disorders. For example, exonic deletions inNRXN1 are associated with ASD, schizophrenia, intellec-tual disability, and language delay [94,95]. Mutations inRPTP-based synaptic organizing complexes also appearto contribute to multiple neuropsychiatric disorders(Table 1). Conversely, one neuropsychiatric disorderinvolves mutations of different genes encoding synapticorganizers. Considering the functional similarities of

RPTP-based complexes to neurexin-based complexes,dysfunction of either type of synaptic organizing complexby subtly altering the composition and function of synap-ses could underlie a common fundamental pathogenesisfor a range of neuropsychiatric disorders.

Concluding remarksThe RPTP family is an emerging presynaptic hub forsynapse organization, molecularly distinct from neurexinsbut remarkably parallel in function and interaction net-work organization. A fundamental outstanding question iswhether RPTPs and neurexins are interdependent forminimal synapse development or whether synapse assem-bly may occur largely independently through the two path-ways. Identifying the intracellular signal transductionpathways mediating synaptic differentiation throughthese complexes is an important next step. Although stud-ies so far have identified many postsynaptic RPTP-bindingpartners, further studies are needed to perform globalidentification of trans-synaptic binding partners of RPTPsand also neurexins in order to delineate the completebinding codes. In addition, the mechanisms mediatingalternative splicing of RPTPs, including cell specificityand activity regulation should be addressed. Given thehub-based design and its possible implications, compre-hensive studies of single- and multi-gene mutant mice,including manipulations of alternatively spliced exons, willbe necessary in order to understand the specific and coop-erative roles of these organizing proteins in synapse devel-opment in multiple circuits and in cognitive functions.Screens for small molecule synaptogenic modulators thatenhance or suppress activity of these synapse organizingproteins [96] represents a promising therapeutic approachfor neuropsychiatric disorders, at least for individuals withmutations in RPTP and neurexin synaptic pathways andperhaps more broadly.

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AcknowledgmentsRelated work by the authors is supported by National Institutes of HealthMH070860, Canadian Institutes of Health Research MOP-125967, andCanada Research Chair awards (to A.M.C.), and a National Alliance forResearch on Schizophrenia and Depression (Brain and BehaviorResearch Fund) Young Investigator award (to H.T.).

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