NGL family PSD-95–interacting adhesion molecules regulate excitatory synapse formation

Kim, Se‐Ho; Burette, A; Chung, Hye Sun; Kwon, Seok-Kyu; Woo, Jooyeon; Lee, Hyun Woo; Kim, Karam; Kim, Hyun; Weinberg, Richard J.; Kim, Eunjoon

doi:10.1038/nn1763

Cited by 247 publications

(309 citation statements)

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“…S2). For each of the five Slitrks, overexpression in cultured hippocampal neurons drastically increased synapse density, monitored as the number of Synapsin I puncta, producing effects similar to those of previously discovered synaptic adhesion molecules, such as neuroligins (NLs), leucinerich repeat transmembrane neuronal proteins (LRRTMs), and NGLs (20)(21)(22) (Fig. 2 A and D).…”

Section: Resultssupporting

confidence: 65%

“…Recent studies have established that a host of neuronal transmembrane proteins containing LRR domains play important roles in synapse development, although the precise functions of these proteins are only slowly being uncovered (3,13,17,20,(25)(26)(27). Six Slitrk family members (Slitrk1-6) share similar domain organizations and have been shown to regulate neurite outgrowth in Pheochromocytoma Cell Line 12 (PC12) cells (5,28).…”

Section: Discussionmentioning

confidence: 99%

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Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

Yim

Kwon

Nam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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161

217

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The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit-and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance.leucine-rich repeat | neuropsychiatic disorder | synaptic cell-adhesion

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Section: Resultssupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

Yim

Kwon

Nam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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161

217

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“…It is intriguing to hypothesize a balance between adhesion systems such as SynCAMs that could guide synaptic development and organization, those that affect both synapse organization and excitatory/inhibitory specificity, such as neurexins and neuroligins, as well as others that promote synapse maturation such as N-cadherins. These transsynaptic interactions are likely rather complex considering the additional roles of postsynaptic SALM (synaptic cell adhesion-like molecule) and NGL proteins and EphB receptors in neuronal and synaptic differentiation (Kayser et al, 2006;Kim et al, 2006;Ko et al, 2006;Wang et al, 2006) and may ultimately not only differentiate but also specify maturing synapses (Benson et al, 2001). On this network level, SynCAM expression differences between neuronal populations combined with their precise heterophilic interaction patterns could contribute to the specificity of synaptic connectivity in addition to organizing individual synapses.…”

mentioning

confidence: 99%

SynCAMs Organize Synapses through Heterophilic Adhesion

Fogel¹,

Akins²,

Krupp³

et al. 2007

J. Neurosci.

188

278

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Synapses are asymmetric cell junctions with precisely juxtaposed presynaptic and postsynaptic sides. Transsynaptic adhesion complexes are thought to organize developing synapses. The molecular composition of these complexes, however, remains incompletely understood, precluding us from understanding how adhesion across the synaptic cleft guides synapse development. Here, we define two immunoglobulin superfamily members, SynCAM 1 and 2, that are expressed in neurons in the developing brain and localize to excitatory and inhibitory synapses. They function as cell adhesion molecules and assemble with each other across the synaptic cleft into a specific, transsynaptic SynCAM 1/2 complex. Additionally, SynCAM 1 and 2 promote functional synapses as they increase the number of active presynaptic terminals and enhance excitatory neurotransmission. The interaction of SynCAM 1 and 2 is affected by glycosylation, indicating regulation of this adhesion complex by posttranslational modification. The SynCAM 1/2 complex is representative for the highly defined adhesive patterns of this protein family, the four members of which are expressed in neurons in divergent expression profiles. SynCAMs 1, 2, and 3 each can bind themselves, yet preferentially assemble into specific, heterophilic complexes as shown for the synaptic SynCAM 1/2 interaction and a second complex comprising SynCAM 3 and 4. Our results define SynCAM proteins as components of novel heterophilic transsynaptic adhesion complexes that set up asymmetric interactions, with SynCAM proteins contributing to synapse organization and function.

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“…Key postsynaptic proteins such as neuroligins, synaptic cell-adhesion molecules (SynCAMs), Ephrin type B (EphB) receptors, netrin G ligands, and leucine-rich repeat transmembrane (LRRTM) proteins signal transsynaptically to induce recruitment of presynaptic components (14)(15)(16)(17)(18)(19)(20). Postsynaptic adhesion molecules also are involved in the functional maturation of presynaptic inputs (21-23).…”

mentioning

confidence: 99%

Regulation of synaptic stability by AMPA receptor reverse signaling

Ripley

Otto

Tiglio

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The establishment of neuronal circuits relies on the stabilization of functionally appropriate connections and the elimination of inappropriate ones. Here we report that postsynaptic AMPA receptors play a critical role in regulating the stability of glutamatergic synapses. Removal of surface AMPA receptors leads to a decrease in the number and stability of excitatory presynaptic inputs, whereas overexpression increases synapse number and stability. Furthermore, overexpression of AMPA receptors along with Neuroligin-1 in 293T cells is sufficient to stabilize presynaptic inputs from cortical neurons onto heterologous cells. The stabilization of presynaptic inputs by AMPA receptors is not dependent on receptor-mediated current and instead relies on structural interactions mediated by the N-terminal domain of the glutamate receptor 2 (GluR2) subunit. These observations indicate that transsynaptic signaling mediated by the extracellular domain of GluR2 regulates the stability of presynaptic terminals.GluR2 N-terminal domain | Presynaptic stabilization | Presynaptic input dynamics T he development of neural circuits is characterized by exuberant synapse formation followed by elimination of inappropriate connections (1-4). Although there is considerable evidence that activity-dependent mechanisms are involved in synapse elimination, the mechanisms responsible for regulating and maintaining stable synapses are largely unknown.Synapse formation is a dynamic process and involves the rapid recruitment of several synaptic proteins to sites of axo-dendritic contact. Transport packets containing essential components of the presynaptic active zone are highly motile before they reach synaptic sites (5). Likewise, synaptic vesicles traffic rapidly along axons before stabilizing at dendritic contact sites (6), suggesting that a dendrite-associated signal regulates presynaptic stability. At glutamatergic synapses, AMPA and NMDA receptors are recruited to the postsynaptic density in 1 h or less (7,8), raising the possibility that they may play an important role in regulating synapse stability.Electrophysiological and immunohistochemical experiments suggest that a large percentage of young synapses contain NMDA receptors but lack AMPA receptors (9, 10). AMPA receptors are recruited gradually to postsynaptic sites, resulting in an increase in the AMPA/NMDA ratio at these synapses (11-13). The increase in the AMPA/NMDA ratio correlates with the stabilization of dendritic spines.Synapse formation requires the precise apposition of presynaptic and postsynaptic elements underlying the need for bidirectional signaling. Key postsynaptic proteins such as neuroligins, synaptic cell-adhesion molecules (SynCAMs), Ephrin type B (EphB) receptors, netrin G ligands, and leucine-rich repeat transmembrane (LRRTM) proteins signal transsynaptically to induce recruitment of presynaptic components (14)(15)(16)(17)(18)(19)(20). Postsynaptic adhesion molecules also are involved in the functional maturation of presynaptic inputs (21-23). Recent work demons...

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NGL family PSD-95–interacting adhesion molecules regulate excitatory synapse formation

Cited by 247 publications

References 50 publications

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

SynCAMs Organize Synapses through Heterophilic Adhesion

Regulation of synaptic stability by AMPA receptor reverse signaling

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