Trans‐synaptic mechanisms orchestrated by mammalian synaptic cell adhesion molecules

Abstract

Bidirectional trans‐synaptic signaling is essential for the formation, maturation, and plasticity of synaptic connections. Synaptic cell adhesion molecules (CAMs) are prime drivers in shaping the identities of trans‐synaptic signaling pathways. A series of recent studies provide evidence that diverse presynaptic cell adhesion proteins dictate the regulation of specific synaptic properties in postsynaptic neurons. Focusing on mammalian synaptic CAMs, this article outlines several exemplary cases supporting this notion and highlights how these trans‐synaptic signaling pathways collectively contribute to the specificity and diversity of neural circuit architecture.

Contrasting synaptic roles of MDGA1 and MDGA2

“…This finding is consistent with the MDGA2-Nlgn2 interaction revealed in our unbiased proteomics. Altogether, our results challenge the model where MDGA1 acts as a specific gatekeeper of inhibitory synapse formation and/or function (20,21,25) and are consistent with a more prominent role at excitatory synapses. Our findings instead indicate that the gatekeeper of inhibitory synapses is MDGA2, which likely involves the regulation of Nlgn2.…”

“…Consistent with cell adhesion and surface bindings assays (12,17), multiple independent groups have provided robust MDGA -neuroligin co-crystal structural data suggesting that MDGAs can sterically block access of neurexins to neuroligins (22)(23)(24). However, this model is primarily based on exogenous overexpression of MDGAs, and despite the reported high affinity of the interaction between MDGA1 and neuroligin-2 (Nlgn2), it remains unclear whether these proteins share overlapping spatial or temporal expression to interact in vivo (25). It is noteworthy that individual neuroligin KOs are not lethal, suggesting that MDGA2, at least in part, performs neuroligin-independent functions.…”

“…1I-K). 4 MDGA proteins are considered synaptic adhesion molecules (16,25,27). However, while some reports have provided evidence of synaptic expression of endogenous MDGAs (13), single molecule imaging studies on overexpressed MDGAs suggest a diffuse localization within dendrites (15).…”

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

“…β-neurexins contain a single LNS domain and no EGF domains. Presynaptic neurexins and Type IIa protein tyrosine phosphatases (RPTPs) interact with a range of postsynaptic ligands to provide synaptic stabilization [ 177 , 178 ]. Neurexin HS interactions with leucine-rich-repeat transmembrane neuronal proteins (LRRTMs) induce presynaptic differentiation and synaptogenesis [ 176 , 179 ].…”