A Normative Model Reveals Functional Optimization of Synaptic Nano-Architecture
- 1Inria center at University of Lorraine, 67000 Strasbourg, France
Abstract
Super-resolution microscopy approaches have revealed that synaptic proteins are not randomly distributed within individual synapses. Rather, they form sub-synaptic clusters that may be coordinated between the synaptic compartments, thereby forming transsynaptic nanocolumns. However, the functional significance of this nano-architecture remains under debate. In particular, it is unclear whether the positions of synaptic proteins optimize a specific cost function. Here, we present a normative modeling framework that integrates synaptic nano-architecture imaged with STED and dSTORM microscopy with synaptic transmission recorded with electrophysiology at the Drosophila neuromuscular junction (NMJ). Model-based quantification showed that clusters of Unc13A, which likely demark presynaptic release sites, and postsynaptic glutamate receptors (GluRs) adopt aligned ring-like arrangements in individual synapses. We developed an analytical description of GluR activation relative to presynaptic release position, enabling to link super-resolution imaging data with recorded postsynaptic current amplitudes without relying on costly Markov chain Monte Carlo (MCMC) simulations. Our model predicts that glutamate released from a single vesicle spreads across the entire receptor population. Given this spread, the postsynaptic current amplitude is maximized when glutamate is released close to the active zone (AZ) center, in contradiction to the observed offset of Unc13A clusters. However, the observed relative positions of Unc13A and GluR clusters maximize the postsynaptic current amplitude and minimize the delay between vesicle release and receptor activation during multivesicular release. Hence, transsynaptically-aligned Unc13A-GluR rings optimize for multivesicular but not univesicular release. Given that multivesicular release is mainly observed during enhanced presynaptic release at the Drosophila NMJ, transsynaptic nano-architecture may be adapted to elevated presynaptic release states.
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BibTeX
@misc{gontier2026normative,
title = {{A Normative Model Reveals Functional Optimization of Synaptic Nano-Architecture}},
author = {C. Gontier and K. Schmidt and M. Baccino-Calace and W. Gauthey and M. Sauer and S. Waeldchen and D. Sachidanandan and R. Kittel and M. Mueller and J.-P. Pfister},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754349},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754349v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Normative Model Reveals Functional Optimization of Synaptic Nano-Architecture
AU - C. Gontier
AU - K. Schmidt
AU - M. Baccino-Calace
AU - W. Gauthey
AU - M. Sauer
AU - S. Waeldchen
AU - D. Sachidanandan
AU - R. Kittel
AU - M. Mueller
AU - J.-P. Pfister
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754349
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754349v1
AB - Super-resolution microscopy approaches have revealed that synaptic proteins are not randomly distributed within individual synapses. Rather, they form sub-synaptic clusters that may be coordinated between the synaptic compartments, thereby forming transsynaptic nanocolumns. However, the functional significance of this nano-architecture remains under debate. In particular, it is unclear whether the positions of synaptic proteins optimize a specific cost function. Here, we present a normative modeling framework that integrates synaptic nano-architecture imaged with STED and dSTORM microscopy with synaptic transmission recorded with electrophysiology at the Drosophila neuromuscular junction (NMJ). Model-based quantification showed that clusters of Unc13A, which likely demark presynaptic release sites, and postsynaptic glutamate receptors (GluRs) adopt aligned ring-like arrangements in individual synapses. We developed an analytical description of GluR activation relative to presynaptic release position, enabling to link super-resolution imaging data with recorded postsynaptic current amplitudes without relying on costly Markov chain Monte Carlo (MCMC) simulations. Our model predicts that glutamate released from a single vesicle spreads across the entire receptor population. Given this spread, the postsynaptic current amplitude is maximized when glutamate is released close to the active zone (AZ) center, in contradiction to the observed offset of Unc13A clusters. However, the observed relative positions of Unc13A and GluR clusters maximize the postsynaptic current amplitude and minimize the delay between vesicle release and receptor activation during multivesicular release. Hence, transsynaptically-aligned Unc13A-GluR rings optimize for multivesicular but not univesicular release. Given that multivesicular release is mainly observed during enhanced presynaptic release at the Drosophila NMJ, transsynaptic nano-architecture may be adapted to elevated presynaptic release states.
ER -