Abstract
Synaptic adhesion-like molecules (SALMs) are a family of cell adhesion molecules involved in regulating neuronal and synapse development that have also been implicated in diverse brain dysfunctions, including autism spectrum disorders (ASDs). SALMs, also known as leucine-rich repeat (LRR) and fibronectin III domain-containing (LRFN) proteins, were originally identified as a group of novel adhesion-like molecules that contain LRRs in the extracellular region as well as a PDZ domain-binding tail that couples to PSD-95, an abundant excitatory postsynaptic scaffolding protein. While studies over the last decade have steadily explored the basic properties and synaptic and neuronal functions of SALMs, a number of recent studies have provided novel insights into molecular, structural, functional and clinical aspects of SALMs. Here we summarize these findings and discuss how SALMs act in concert with other synaptic proteins to regulate synapse development and function.
Highlights
Synaptic adhesion-like molecules (SALMs), known as leucine-rich repeat (LRR) and fibronectin III domain-containing (LRFN) proteins, are a family of synaptic adhesion molecules originally identified independently by three groups as novel cell adhesion-like molecules that bind through their C-terminal tails to the PDZ domains of postsynaptic density (PSD)-95 (Ko et al, 2006; Morimura et al, 2006; Wang et al, 2006; Nam et al, 2011), an abundant excitatory postsynaptic scaffolding protein (Sheng and Kim, 2011)
These results give rise to a number of obvious questions: Why are there multiple LAR-RPTP-binding postsynaptic adhesion molecules? Does a single synapse contain all, or a majority, of the postsynaptic LAR-RPTP ligands? If so, do they compete with each other for mutually exclusive LAR-RPTP binding, or do they act in concert to fine-tune synapse regulation? These questions can be applied to the three presynaptic LARRPTPs, LAR, PTPσ and PTPδ
Immunogold electron microscopy has revealed strong colocalization of SALM1 with the GluN1 subunit of N-methyl-D-aspartate receptors (NMDARs) (Thevenon et al, 2016). These results suggest that SALM1 promotes synaptic clustering of NMDARs, in vivo support for these findings has been lacking
Summary
Synaptic adhesion molecules play important roles in the regulation of various processes involved in synapse development and function, including early axo-dendritic contacts, maturation of early synapses, synaptic transmission and plasticity, and synapse maintenance and elimination (Dalva et al, 2007; Biederer and Stagi, 2008; Han and Kim, 2008; Sanes and Yamagata, 2009; Woo et al, 2009b; Shen and Scheiffele, 2010; Siddiqui and Craig, 2011; Krueger et al, 2012; Missler et al, 2012; Valnegri et al, 2012; Takahashi and Craig, 2013; Um and Ko, 2013, 2017; Bemben et al, 2015; Ko J. et al, 2015; de Wit and Ghosh, 2016; Cao and Tabuchi, 2017; Jang et al, 2017; Krueger-Burg et al, 2017; Sudhof, 2017; Yuzaki, 2018). This review article will summarize these new findings and discuss how SALMs regulate synapse development and function
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