Abstract
It has long been proposed that leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cell-adhesion proteins that control synapse assembly. Their synaptic nanoscale localization, however, is not established, and synapse fine structure after knockout of the three vertebrate LAR-RPTPs (PTPδ, PTPσ, and LAR) has not been tested. Here, superresolution microscopy reveals that PTPδ localizes to the synaptic cleft precisely apposed to postsynaptic scaffolds of excitatory and inhibitory synapses. We next assessed synapse structure in newly generated triple-conditional-knockout mice for PTPδ, PTPσ, and LAR, complementing a recent independent study of synapse function after LAR-RPTP ablation (Sclip and Südhof, 2020). While mild effects on synaptic vesicle clustering and active zone architecture were detected, synapse numbers and their overall structure were unaffected, membrane anchoring of the active zone persisted, and vesicle docking and release were normal. Hence, despite their localization at synaptic appositions, LAR-RPTPs are dispensable for presynapse structure and function.
Highlights
Presynaptic nerve terminals are packed with neurotransmitter-laden vesicles that fuse at the active zone, membrane-attached protein machinery that forms vesicular release sites
Cre recombinase was delivered at DIV6 by lentiviruses and expressed from a Synapsin promotor (Liu et al, 2014) and resulted in removal of PTPd, PTPs, and LAR, generating cTKORPTP neurons (Figure 1A,B)
Data are plotted as mean ± SEM and were analyzed using two-way ANOVA tests (F, I, genotype *** for PTPd), t-tests (E, L, M) or Mann-Whitney rank sum tests (H, K). **p
Summary
Presynaptic nerve terminals are packed with neurotransmitter-laden vesicles that fuse at the active zone, membrane-attached protein machinery that forms vesicular release sites. Three LAR-RPTPs – PTPd, PTPs, and LAR – are expressed in the brain, bind to the active zone scaffolding protein Liprin-a and to synaptic cell-adhesion proteins, and recruit presynaptic material in artificial synapse formation assays (Bomkamp et al, 2019; Han et al, 2018; Han et al, 2020a; Johnson and Van Vactor, 2003; Kwon et al, 2010; Pulido et al, 1995; Serra-Pages et al, 1998; Takahashi et al, 2011; Yim et al, 2013). Analyses of active zone protein composition, synapse ultrastructure, and synaptic transmission in newly generated conditional PTPd/PTPs/LAR triple-knockout mice reveal that these proteins are largely dispensable for synapse structure and function
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