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

Abstract

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

Septin 6 Regulates the Cytoarchitecture of Neurons through Localization at Dendritic Branch Points and Bases of Protrusions

“…The SV2 is a component of all vertebrate synaptic vesicles (Buckley and Kelly, 1985), and the presynaptic accumulation of synaptic vesicles is a hallmark process in synaptic maturation (Garner et al, 2006). One mechanism for pre-synaptic vesicle clustering is the retrograde signaling via trans-synaptic adhesion molecules in contact with the post-synaptic structure (Scheiffele et al, 2000;Stan et al, 2010). Therefore, our data imply that SEPT6 accumulates in the axonal boutons as the boutons mature upon post-synaptic contact.…”

Structural Components of Synaptic Plasticity and Memory Consolidation

“…For example, presynaptic neurexin-1b (Nrx-1b) has two postsynaptic partners, neuroligin-1 (NLG-1) and postsynaptic leucine-rich repeat transmembrane protein 2 (LRRTM2). This extracellular binding modulates presynaptic vesicle release and promotes synapse initiation and stabilization together with N-cadherin (Ichtchenko et al 1995;Song et al 1999;Scheiffele et al 2000;Dean et al 2003;Graf et al 2004;Futai et al 2007;Heine et al 2008;Sudhof 2008;deWit et al 2009;Linhoff et al 2009;Wittenmayer et al 2009;Stan et al 2010;Soler-Llavina et al 2013). Furthermore, the Nrx-1b/NLG-1 complex binds with PSD-95, Stargazin, and other proteins that reduce AMPAR diffusion (Irie et al 1997;Barrow et al 2009;Mondin et al 2011;Giannone et al 2013).…”

The classic cadherins in synaptic specificity

“…Previous studies found an indirect biochemical link between neuroligins and N-cadherin via S-SCAM and b-catenin [84][85][86] and more recent results from 2 different groups show that Ncadherin is necessary to cluster neuroligin-1 at synaptic sites. 77,78 Thus, overexpression of neuroligin-1 is synaptogenic, but only in the presence of N-cadherin. 77,78 Together, these 2 cell adhesion systems promote the clustering of synaptic vesicles and increase the probability of synaptic vesicle release.…”