Intact synapse structure and function after combined knockout of PTPδ, PTPσ, and LAR

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.

The cell biology of synapse formation

“…Moreover, LAR-PTPRs appear to interact with neurexins in cis, possibly via the heparan-sulfate modification of neurexins ( Han et al, 2020 ). Deletion of all three LAR-PTPRs causes no decrease in synapse numbers, demonstrating that they alone are not essential for making a synapse, but induce an ∼40% decrease in NMDAR-mediated synaptic responses without significantly altering AMPAR-mediated responses ( Sclip and Südhof, 2020 ; Emperador-Melero et al, 2021 ). Although this phenotype resembles the effect of neurexin-1 SS4-alternative splicing on NMDAR-mediated synaptic responses, in the case of neurexin-1, the surface levels of NMDARs are changed ( Dai et al, 2019 ), whereas in the case of the LAR-PTPR deletion, the surface levels of NMDARs were not impaired ( Sclip and Südhof, 2020 ).…”

Synaptic promiscuity in brain development

“…Indeed, both LARs and Neurexins are strongly synaptogenic 119 , 120 . Surprisingly, however, neither LARs nor Neurexins appear to be generally required for synapse formation, supporting the notion of molecular redundancies 121 , 122 . Not even loss of three neurexins or all three LARs in mice appears to reduce synapse numbers, whereas only a conditional sixtuple-knockout of these LARs and Neurexins leads to an at least 50% reduction of synapse numbers between Purkinje cells and deep cerebellar nuclei 118 .…”

Molecular mechanisms of synaptogenesis

“…Mice lacking RPTσ , on the contrary, showed increased synapse density ( Horn et al, 2012 ). Studies on triple knockout mice either in vivo using virus carrying Cre recombinase or in cultured neurons showed that PTPδ , PTPσ , and LAR triple knockout do not affect the development and function of synapses ( Sclip and Sudhof, 2020 ; Emperador-Melero et al, 2021 ).…”