How to build a central synapse: clues from cell culture

Craig, Ann Marie; Graf, Ethan R.; Linhoff, Michael W.

doi:10.1016/j.tins.2005.11.002

Cited by 164 publications

(153 citation statements)

References 145 publications

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“…Members of the PSD-95 family of membrane-associated guanylate kinases, and particularly PSD-95 itself, are highly enriched at the postsynaptic density and are thought to play a role in clustering proteins with PDZ-BDs at the synapse. However, whereas SALMs 1-3 are present at the PSD, their distributions are more general than that of PSD-95 (11), 3 Labeling for SALM4 is found on the cell membrane of processes in the brain (arrowheads). A-C, P10 CA1 stratum radiatum of the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

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The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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Synaptic adhesion-like molecules (SALMs) are a newly discovered family of adhesion molecules that play roles in synapse formation and neurite outgrowth. The SALM family is comprised of five homologous molecules that are expressed largely in the central nervous system. SALMs 1-3 contain PDZ-binding domains, whereas SALMs 4 and 5 do not. We are interested in characterizing the interactions of the SALMs both among the individual members and with other binding partners. In the present study, we focused on the interactions formed by the five SALM members in rat brain and heterologous cells. In brain, we found that SALMs 1-3 strongly co-immunoprecipitated with each other, whereas SALMs 4 and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes. In heterologous cells transfected with SALMs, co-immunoprecipitation studies showed that all five SALMs form heteromeric and homomeric complexes. We also determined if SALMs could form trans-cellular associations between transfected heterologous cells. Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. The ability of SALM4 to form trans interactions is due to its extracellular N terminus because chimeras of SALM4 N terminus and SALM2 C terminus can form trans interactions, whereas chimeras of SALM2 N terminus and SALM4 C terminus cannot. Co-culture experiments using HeLa cells and rat hippocampal neurons expressing the SALMs showed that SALM4 is recruited to points of contact between the cells. In neurons, these points of contact were seen in both axons and dendrites.Critical steps in the development of the nervous system, including cell migration, neurite outgrowth, growth cone guidance, and synapse formation, depend on cellular interactions mediated by adhesion molecules (1-4). A number of adhesion molecules that are essential to the proper development of the nervous system have been identified (5-7). The importance of these molecules is illustrated in cases of dysfunctional adhesion molecules that have been associated with specific disorders in humans, including SLITRK1 in Tourette syndrome (8) and neuroligin in autism (9, 10). Whereas our understanding of the role of adhesion molecules in neuronal development is rapidly increasing, little is known about their functions, and it is likely that many remain to be identified.Synaptic adhesion-like molecules (SALMs) 2 are a recently identified class of adhesion molecules that are highly enriched in brain (11-13). All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail. SALMs 1-3 contain a C-terminal PDZ-binding domain (PDZ-BD), which associates with the PSD-95 family of proteins (11-13). SALMs are expressed early in the developing nervous system and persist into adulthood. They are present at the synaptic membrane as well as at non-synaptic locations. SALM1 overe...

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Section: Discussionmentioning

confidence: 99%

“…Critical steps in the development of the nervous system, including cell migration, neurite outgrowth, growth cone guidance, and synapse formation, depend on cellular interactions mediated by adhesion molecules (1)(2)(3)(4). A number of adhesion molecules that are essential to the proper development of the nervous system have been identified (5)(6)(7).…”

mentioning

confidence: 99%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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“…At the synapse, presynaptic and postsynaptic membranes are linked together by a variety of adhesion molecules 1 . Two adhesion molecules that have been implicated in the establishment and maturation of synaptic contacts are neuroligins, which are postsynaptic proteins, and neurexins, which are presynaptic proteins [2][3][4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Chen

Liu

Shim

et al. 2007

Nat Struct Mol Biol

147

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The heterophilic synaptic adhesion molecules, neuroligins and neurexins, are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca 2+ -dependent and regulated by alternative splicing. We report a 2.4Å structure of the complex between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin 1β (NX1β) LNS (laminins, neurexins, and sex hormone-binding globulin-like) domain. The structure reveals a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca 2+ -mediated, and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data support a mechanism where splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1β interface. Mapping neuroligin mutations implicated in autism indicates most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.

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“…Synaptogenesis follows the specification of cell-to-cell contacts mediated by cell adhesion molecules (1,2) and involves the initiation of chemical communication through the recruitment of pre-and postsynaptic proteins necessary for fast synaptic transmission (3,4), such as AMPA receptors (AMPARs) and NMDA receptors (NMDARs). Synapse maturation is characterized by two functional events: an increase in the strength of AMPAR-mediated transmission (5,6) and a switch in the subunit composition of synaptic NMDARs (7).…”

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confidence: 99%

Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development

Elias

Apostolides

et al. 2008

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

196

190

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The development of glutamatergic synapses involves changes in the number and type of receptors present at the postsynaptic density. To elucidate molecular mechanisms underlying these changes, we combine in utero electroporation of constructs that alter the molecular composition of developing synapses with dual whole-cell electrophysiology to examine synaptic transmission during two distinct developmental stages. We find that SAP102 mediates synaptic trafficking of AMPA and NMDA receptors during synaptogenesis. Surprisingly, after synaptogenesis, PSD-95 assumes the functions of SAP102 and is necessary for two aspects of synapse maturation: the developmental increase in AMPA receptor transmission and replacement of NR2B-NMDARs with NR2A-NMDARs. In PSD-95/PSD-93 double-KO mice, the maturational replacement of NR2B-with NR2A-NMDARs fails to occur, and PSD-95 expression fully rescues this deficit. This study demonstrates that SAP102 and PSD-95 regulate the synaptic trafficking of distinct glutamate receptor subtypes at different developmental stages, thereby playing necessary roles in excitatory synapse development.AMPAR and NMDAR trafficking ͉ membrane-associated guanylate kinase ͉ synaptogenesis ͉ postsynaptic density ͉ synaptic transmission A fundamental goal of developmental neurobiology is to identify the sequence of molecular events underlying excitatory synapse development, a process that can be divided into two distinct stages: synaptogenesis and synapse maturation. Synaptogenesis follows the specification of cell-to-cell contacts mediated by cell adhesion molecules (1, 2) and involves the initiation of chemical communication through the recruitment of pre-and postsynaptic proteins necessary for fast synaptic transmission (3, 4), such as AMPA receptors (AMPARs) and NMDA receptors (NMDARs). Synapse maturation is characterized by two functional events: an increase in the strength of AMPAR-mediated transmission (5, 6) and a switch in the subunit composition of synaptic NMDARs (7). NMDARs are composed of two obligatory NR1 subunits and two NR2 subunits, of which there are four members (NR2A-D) (8). NR2B-NMDARs are expressed during synaptogenesis and are replaced by NR2A-NMDARs during synapse maturation (9-11), a replacement that accounts for the developmental decrease in the NMDAR excitatory postsynaptic current (EPSC) decay time (12, 13) and the loss of sensitivity to the NR2B antagonist ifenprodil (14). The precise molecular mechanisms underlying the differential synaptic trafficking of AMPAR and NMDAR during developmental synaptogenesis and maturation remain largely unknown.PSD-95 is a member of a family of proteins collectively known as membrane-associated guanylate kinases (MAGUKs) (15-17). The PSD-95-like subfamily of neuronal MAGUKs (PSD-MAGUKs) includes PSD-93, SAP102, and SAP97 (15-17). Comparative studies emphasize the remarkable similarities among PSD-MAGUKs in terms of protein-protein interactions (18,19) and overlapping functions in synaptic trafficking of AMPARs at mature synapses (20-24). On the ot...

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How to build a central synapse: clues from cell culture

Cited by 164 publications

References 145 publications

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development

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