Redundant Postsynaptic Functions of SynCAMs 1–3 during Synapse Formation

Abstract

Investigating the roles of synaptogenic adhesion molecules during synapse formation has proven challenging, often due to compensatory functions between additional family members. The synaptic cell adhesion molecules 1–3 (SynCAM1–3) are expressed both pre- and postsynaptically, share highly homologous domains and are synaptogenic when ectopically presented to neurons; yet their endogenous functions during synaptogenesis are unclear. Here we report that SynCAM1–3 are functionally redundant and collectively necessary for synapse formation in cultured hippocampal neurons. Only triple knockdown (KD) of SynCAM1–3 using highly efficient, chained artificial microRNAs (amiRNAs) reduced synapse density and increased synapse area. Electrophysiological recordings of quantal release events supported an increase in synapse size caused by SynCAM1–3 depletion. Furthermore, a combinatorial, mosaic lentiviral approach comparing wild type (WT) and SynCAM1–3 KD neurons in the same culture demonstrate that SynCAM1–3 set synapse number and size through postsynaptic mechanisms. The results demonstrate that the redundancy between SynCAM1–3 has concealed their synaptogenic function at the postsynaptic terminal.

Oligodendrocytes express synaptic proteins that modulate myelin sheath formation

“…Thus, Cadm1b might have distinct signaling and adhesion-based functions in myelin sheath growth. Although we did not find evidence that disruption of Cadm1b function alters presynaptic assembly, as manifested by axonal vesicle clustering, multiple transsynaptic adhesion systems are thought to operate in parallel at synapses 60,61 , and redundancy within and between families can obscure how individual adhesion proteins contribute to synapse formation. Intriguingly, oligodendrocyte expression of a Cadm4 variant, a protein with structural similarity to Cadm1b, consisting of the extracellular and transmembrane domains, predicted to promote adhesion, resulted in a large excess of short sheaths 62 .…”

Axoglial Adhesion by Cadm4 Regulates CNS Myelination

“…Cadm4 mediates internodal axoglial adhesion by binding to axonal Cadm2 and Cadm3 in both the peripheral (Maurel et al, 2007;Spiegel et al, 2007) and the central (Pellissier et al, 2007;Sharma et al, 2015; Figure S4A) nervous systems. However, in line with the presence of multiple members of this family in both neurons and myelinating glia and their combinatorial heterophilic binding properties, as well as their redundant function in other systems (Fowler et al, 2017), genetic deletion of individual Cadm genes in mice resulted in only marginal myelination phenotypes (Golan et al, 2013;Park et al, 2008;Zhu et al, 2013). By using a different experimental approach that relies on the expression of the extracellular domain of Cadm4 in OLs, we reveal a critical role for cell adhesion in myelin targeting, membrane wrapping, and lateral extension of the myelin sheath.…”

A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity

“…Inputs Studies in cultured neurons indicated redundancy between synaptic adhesion molecules of the SynCAM family (Fowler et al, 2017) and between neuroligins (Nlgns) and LRRTMs (Ko et al, 2011). These studies assessed the effect of combinatorial loss of postsynaptic adhesion proteins that bind to common presynaptic receptors (SynCAMs in the case of SynCAMs, Biederer et al, 2002;Nrxn for Nlgns and LRRTMs, Krueger et al, 2012), which might result in partial functional convergence.…”