Structural and Functional Alterations of Neuromuscular Junctions in NCAM-Deficient Mice

Rafuse, Victor F.; Polo‐Parada, Luis; Landmesser, Lynn T.

doi:10.1523/jneurosci.20-17-06529.2000

Cited by 114 publications

(92 citation statements)

References 62 publications

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“…Thus, our functional analysis of N-cadherin knock-out synapses revealed an unexpected involvement of N-cadherin in the regulation of short-term plasticity at glutamatergic synapses. An analogous phenotype consisting of enhanced synaptic depression during repetitive stimulation was described in neural cell adhesion molecule (NCAM)-deficient mouse neuromuscular synapses (Rafuse et al, 2000).…”

Section: Discussionmentioning

confidence: 77%

N-Cadherin Transsynaptically Regulates Short-Term Plasticity at Glutamatergic Synapses in Embryonic Stem Cell-Derived Neurons

et al. 2006

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The cell adhesion molecule N-cadherin has been proposed to regulate synapse formation in mammalian central neurons. This is based on its synaptic localization enabling alignment of presynaptic and postsynaptic specializations by an adhesion mechanism. However, a potential role of N-cadherin in regulating synaptic transmission has remained elusive. In this paper, a functional analysis of N-cadherin knock-out synapses was enabled by in vitro neuronal differentiation of mouse embryonic stem cells circumventing the early embryonic lethality of mice genetically null for N-cadherin. In our in vitro system, initial synapse formation was not altered in the absence of N-cadherin, which might be attributable to compensatory mechanisms. Here, we demonstrate that N-cadherin is required for regulating presynaptic function at glutamatergic synapses. An impairment in the availability of vesicles for exocytosis became apparent selectively during high activity. Short-term plasticity was strongly altered with synaptic depression enhanced in the absence of N-cadherin. Most intriguingly, facilitation was converted to depression under specific stimulation conditions. This indicates an important role of N-cadherin in the control of short-term plasticity.To analyze, whether N-cadherin regulates presynaptic function by a transsynaptic mechanism, we studied chimeric cultures consisting of wild-type neocortical neurons and ES cell-derived neurons. With N-cadherin absent only postsynaptically, we observed a similar increase in short-term synaptic depression as found in its complete absence. This indicates a retrograde control of short-term plasticity by N-cadherin. In summary, our results revealed an unexpected involvement of a synaptic adhesion molecule in the regulation of short-term plasticity at glutamatergic synapses.

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Section: Discussionmentioning

confidence: 77%

N-Cadherin Transsynaptically Regulates Short-Term Plasticity at Glutamatergic Synapses in Embryonic Stem Cell-Derived Neurons

et al. 2006

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“…In addition, β-catenin-(19) and p120catenin-deficient (17) hippocampal neurons showed a reduced clustering of presynaptic vesicles. At the neuromuscular junction, the adhesion molecule NCAM has been described to play an analogous role (34). Direct presynaptic catenin signaling via the actin cytoskeleton and via cytoplasmic proteins has been proposed to mediate the regulation of vesicle clustering by the N-cadherin/ catenin system (17,19,35).…”

Section: Discussionmentioning

confidence: 99%

Essential cooperation of N-cadherin and neuroligin-1 in the transsynaptic control of vesicle accumulation

Stan¹,

Pielarski²,

Brigadski

et al. 2010

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

117

116

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Cell adhesion molecules are key players in transsynaptic communication, precisely coordinating presynaptic differentiation with postsynaptic specialization. At glutamatergic synapses, their retrograde signaling has been proposed to control presynaptic vesicle clustering at active zones. However, how the different types of cell adhesion molecules act together during this decisive step of synapse maturation is largely unexplored. Using a knockout approach, we show that two synaptic adhesion systems, N-cadherin and neuroligin-1, cooperate to control vesicle clustering at nascent synapses. Live cell imaging and fluorescence recovery after photobleaching experiments at individual synaptic boutons revealed a strong impairment of vesicle accumulation in the absence of N-cadherin, whereas the formation of active zones was largely unaffected. Strikingly, also the clustering of synaptic vesicles triggered by neuroligin-1 overexpression required the presence of N-cadherin in cultured neurons. Mechanistically, we found that N-cadherin acts by postsynaptically accumulating neuroligin-1 and activating its function via the scaffolding molecule S-SCAM, leading, in turn, to presynaptic vesicle clustering. A similar cooperation of N-cadherin and neuroligin-1 was observed in immature CA3 pyramidal neurons in an organotypic hippocampal network. Moreover, at mature synapses, N-cadherin was required for the increase in release probability and miniature EPSC frequency induced by expressed neuroligin-1. This cooperation of two cell adhesion systems provides a mechanism for coupling bidirectional synapse maturation mediated by neuroligin-1 to cell type recognition processes mediated by classical cadherins.synapse maturation | synaptic adhesion molecules | vesicle clustering

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“…The use of lipophilic dyes, such as FM1-43 and FM2-20, in living cells provides a powerful way to assess different SV pools in individual nerve terminals (Kraszewski et al, 1996;Kuromi and Kidokoro, 1998;Cochilla et al, 1999;Quigley et al, 1999;Rafuse et al, 2000;Richards et al, 2000). Using this model, we designed a vital staining strategy incorporating the zinc-indicator zinquin (Zalewski et al, 1993(Zalewski et al, , 1994Snitsarev et al, 2001) and the pH-indicator LysoSensor Green DND-189 (Lin et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…The extent of overlapping is likely determined by the relative proportion of endosomal and plasma membrane routes present in a cell domain (Zakharenko et al, 1999), the developmental status of the cell (Rafuse et al, 2000), the affinities of the synaptic vesicle proteins for different adaptors, the association of several vesicle antigens in complexes with other SV proteins (Bennett et al, 1992), the lipid composition of the membrane (Mitter et al, 2003), and the functional status of the synapse (Heuser and Reese, 1973).…”

Section: Discussionmentioning

confidence: 99%

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Salazar

Love

Werner

et al. 2004

MBoC

112

178

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Synaptic vesicles (SV) are generated by two different mechanisms, one AP-2 dependent and one AP-3 dependent. It has been uncertain, however, whether these mechanisms generate SV that differ in molecular composition. We explored this hypothesis by analyzing the targeting of ZnT3 and synaptophysin both to PC12 synaptic-like microvesicles (SLMV) as well as SV isolated from wild-type and AP-3-deficient mocha brains. ZnT3 cytosolic tail interacted selectively with AP-3 in cell-free assays. Accordingly, pharmacological disruption of either AP-2-or AP-3-dependent SLMV biogenesis preferentially reduced synaptophysin or ZnT3 targeting, respectively; suggesting that these antigens were concentrated in different vesicles. As predicted, immuno-isolated SLMV revealed that ZnT3 and synaptophysin were enriched in different vesicle populations. Likewise, morphological and biochemical analyses in hippocampal neurons indicated that these two antigens were also present in distinct but overlapping domains. ZnT3 SV content was reduced in AP-3-deficient neurons, but synaptophysin was not altered in the AP-3 null background. Our evidence indicates that neuroendocrine cells assemble molecularly heterogeneous SV and suggests that this diversity could contribute to the functional variety of synapses. INTRODUCTIONThe molecular diversity in total brain synaptic vesicle (SV) composition is generally presumed to result from differential expression of synaptic vesicle membrane proteins in different brain regions. However, the possibility that synaptic vesicles differ in composition because of different biogenesis mechanisms has not been explored. Different vesiculation pathways could result in molecularly diverse synaptic vesicles. Vesiculation mechanisms are known to produce distinct cargo carriers from a population of donor membranes (Bonifacino and Dell'Angelica, 1999;Springer et al., 1999;Boehm and Bonifacino, 2001). This process is achieved by adaptor complexes that recognize and concentrate specific membrane proteins in the donor membranes (Bonifacino and Dell 'Angelica, 1999;Kirchhausen, 1999). PC12 cells have been shown to possess two such adaptor-dependent pathways for the assembly of synaptic vesicles, also known as synaptic-like microvesicles (SLMV) (Shi et al., 1998;de Wit et al., 1999;Jarousse and Kelly, 2001). In one pathway, SLMV are generated from the plasma membrane by a vesiculation mechanism that requires the adaptor AP-2, clathrin, and the GTPase dynamin (Shi et al., 1998). In the second pathway, SLMV are generated from endosomes by the adaptor complex AP-3 (Faundez et al., 1998;Blumstein et al., 2001) and the GTPase ARF1 (Faundez et al., 1997). In contrast to the plasma membrane pathway, the endosomederived mechanism is highly sensitive to brefeldin A (BFA) (Shi et al., 1998).Phenotypes observed in the AP-3-deficient mocha mouse are consistent with a role for the AP-3-dependent, endosome-derived pathway in neurons (Kantheti et al., 1998). The mocha mossy fibers are devoid of both the synaptic vesiclespecific zinc transpor...

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Structural and Functional Alterations of Neuromuscular Junctions in NCAM-Deficient Mice

Cited by 114 publications

References 62 publications

N-Cadherin Transsynaptically Regulates Short-Term Plasticity at Glutamatergic Synapses in Embryonic Stem Cell-Derived Neurons

N-Cadherin Transsynaptically Regulates Short-Term Plasticity at Glutamatergic Synapses in Embryonic Stem Cell-Derived Neurons

Essential cooperation of N-cadherin and neuroligin-1 in the transsynaptic control of vesicle accumulation

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

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