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bioRxiv · 10.64898/2026.10.21.760724

Nanoarchitecture of the presynaptic cell adhesion molecule PTPσ in relation to prospective vesicle fusion sites and postsynaptic NMDA receptors

DeMarco Hibbs, E. M.·Mitias, S.·Aitken, R.·Levy, A. D.·Blanpied, T. A.
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Abstract

Protein organization at individual synapses tunes synaptic function. Presynaptic release-regulating proteins and postsynaptic receptors each concentrate into subsynaptic nanoclusters, and their precise alignment across the cleft into nanocolumns can maximize receptor activation following vesicle fusion. However, both the molecular organization defining presynaptic fusion sites and the mechanisms by which they are spatially coordinated with postsynaptic complexes remains unclear. Presynaptic transmembrane cell adhesion molecules may mediate both processes as they could simultaneously anchor cytosolic fusion machinery to the presynaptic membrane and bridge the cleft to coordinate PSD organization. The LAR-RPTP family member PTP{sigma} is an important possibility, as its trans-synaptic interactors that bind PSD-95 are associated with NMDAR dysfunction, suggesting PTP{sigma} may coordinate NMDAR positioning. However, PTP{sigma}'s subsynaptic organization has not been determined. Here, we investigate the cellular expression and subsynaptic nano-organization of endogenous PTP{sigma} in cultured rat hippocampal neurons. We find that PTP{sigma} is enriched at most excitatory synapses, but unexpectedly, PTP{sigma} nanoclusters do not colocalize with the vesicle priming protein Munc13-1. Instead, they adopt a stereotyped position adjacent to this machinery, without preferential association with sites in nanocolumns. PTP{sigma} nanoclusters also lie offset from postsynaptic NMDA receptors, mirroring their relationship to vesicle fusion sites, yet the presence of PTP{sigma} at a nanocolumn does not predict NMDAR abundance. Together, these findings suggest that PTP{sigma} does not directly coordinate release site - NMDAR alignment but instead occupies defined nanoscale positions adjacent to vesicle fusion sites, potentially helping to shape or stabilize the vesicle priming landscape of the active zone.

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DeMarco Hibbs, E. M., Mitias, S., Aitken, R., Levy, A. D., Blanpied, T. A.. 2026-10-25. Nanoarchitecture of the presynaptic cell adhesion molecule PTPσ in relation to prospective vesicle fusion sites and postsynaptic NMDA receptors. https://doi.org/10.64898/2026.10.21.760724

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