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MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior

Andrea Toledo, Giorgia Bimbi, Mathieu Letellier, Béatrice Tessier, Sophie Daburon, Alexandre Favereaux, Ingrid Chamma, Kristel M. Vennekens, Jeroen Vanderlinden, Matthieu Sainlos, Joris de Wit, Daniel Choquet, Olivier Thoumine
doi: https://doi.org/10.1101/2021.03.16.435652
Andrea Toledo
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Giorgia Bimbi
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Mathieu Letellier
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Béatrice Tessier
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Sophie Daburon
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Alexandre Favereaux
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Ingrid Chamma
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Kristel M. Vennekens
2VIB Center for Brain & Disease Research and KU Leuven, Department of Neurosciences, Leuven Brain Institute, Herestraat, Leuven, Belgium
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Jeroen Vanderlinden
2VIB Center for Brain & Disease Research and KU Leuven, Department of Neurosciences, Leuven Brain Institute, Herestraat, Leuven, Belgium
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Matthieu Sainlos
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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Joris de Wit
2VIB Center for Brain & Disease Research and KU Leuven, Department of Neurosciences, Leuven Brain Institute, Herestraat, Leuven, Belgium
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Daniel Choquet
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
3Univ. Bordeaux, CNRS, INSERM, Bordeaux Imaging Center, BIC, UMS 3420, US 4, F-33000 Bordeaux, France
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Olivier Thoumine
1Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France
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  • For correspondence: olivier.thoumine@u-bordeaux.fr
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Abstract

MDGAs are molecules that can bind neuroligins in cis and interfere with trans-synaptic neurexin-neuroligin interactions, thereby impairing synapse development. However, the sub-cellular localization and dynamics of MDGAs, as well as their specific mode of action in neurons are still unclear. Here, using both surface immunostaining of endogenous MDGAs and single molecule tracking of recombinant MDGAs in dissociated hippocampal neurons, we show that MDGA1 and MDGA2 molecules are homogeneously distributed and exhibit fast membrane diffusion, with a small reduction in mobility across neuronal maturation in culture Using shRNAs and CRISPR/Cas9 strategies to knock-down/out MDGA1 or MDGA2, we demonstrate an increase in the density of excitatory synapses accompanied by enhanced membrane immobilization and an increase in the phosphotyrosine level of neuroligins associated with excitatory post-synaptic differentiation. Finally, we show that decreasing MDGA expression level reduces the mobility of AMPA receptors and increases the frequency of AMPA receptor mediated mEPSCs. Overall, our results support a mechanism by which interactions between MDGAs and neuroligin-1 delays the assembly of functional excitatory synapses containing AMPA receptors.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Co-senior authors

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Posted March 17, 2021.
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MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior
Andrea Toledo, Giorgia Bimbi, Mathieu Letellier, Béatrice Tessier, Sophie Daburon, Alexandre Favereaux, Ingrid Chamma, Kristel M. Vennekens, Jeroen Vanderlinden, Matthieu Sainlos, Joris de Wit, Daniel Choquet, Olivier Thoumine
bioRxiv 2021.03.16.435652; doi: https://doi.org/10.1101/2021.03.16.435652
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MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior
Andrea Toledo, Giorgia Bimbi, Mathieu Letellier, Béatrice Tessier, Sophie Daburon, Alexandre Favereaux, Ingrid Chamma, Kristel M. Vennekens, Jeroen Vanderlinden, Matthieu Sainlos, Joris de Wit, Daniel Choquet, Olivier Thoumine
bioRxiv 2021.03.16.435652; doi: https://doi.org/10.1101/2021.03.16.435652

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