MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior
MDGA molecules can bind neuroligins and interfere with trans-synaptic interactions to neurexins, thereby impairing synapse development. However, the subcellular localization and dynamics of MDGAs, or their specific action mode in neurons remain unclear. Here, surface immunostaining of endogenous MDG...
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| Format: | Article |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75233 |
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| author | Andrea Toledo Mathieu Letellier Giorgia Bimbi Béatrice Tessier Sophie Daburon Alexandre Favereaux Ingrid Chamma Kristel Vennekens Jeroen Vanderlinden Matthieu Sainlos Joris de Wit Daniel Choquet Olivier Thoumine |
| author_facet | Andrea Toledo Mathieu Letellier Giorgia Bimbi Béatrice Tessier Sophie Daburon Alexandre Favereaux Ingrid Chamma Kristel Vennekens Jeroen Vanderlinden Matthieu Sainlos Joris de Wit Daniel Choquet Olivier Thoumine |
| author_sort | Andrea Toledo |
| collection | DOAJ |
| description | MDGA molecules can bind neuroligins and interfere with trans-synaptic interactions to neurexins, thereby impairing synapse development. However, the subcellular localization and dynamics of MDGAs, or their specific action mode in neurons remain unclear. Here, surface immunostaining of endogenous MDGAs and single molecule tracking of recombinant MDGAs in dissociated hippocampal neurons reveal that MDGAs are homogeneously distributed and exhibit fast membrane diffusion, with a small reduction in mobility across neuronal maturation. Knocking-down/out MDGAs using shRNAs and CRISPR/Cas9 strategies increases the density of excitatory synapses, the membrane confinement of neuroligin-1, and the phosphotyrosine level of neuroligins associated with excitatory post-synaptic differentiation. Finally, MDGA silencing reduces the mobility of AMPA receptors, increases the frequency of miniature EPSCs (but not IPSCs), and selectively enhances evoked AMPA-receptor-mediated EPSCs in CA1 pyramidal neurons. Overall, our results support a mechanism by which interactions between MDGAs and neuroligin-1 delays the assembly of functional excitatory synapses containing AMPA receptors. |
| first_indexed | 2024-04-12T16:32:27Z |
| format | Article |
| id | doaj.art-ed4ed58b731048d6a93d60b138a1317d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:32:27Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-ed4ed58b731048d6a93d60b138a1317d2022-12-22T03:25:06ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.75233MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behaviorAndrea Toledo0Mathieu Letellier1https://orcid.org/0000-0003-4008-298XGiorgia Bimbi2Béatrice Tessier3Sophie Daburon4Alexandre Favereaux5Ingrid Chamma6Kristel Vennekens7Jeroen Vanderlinden8Matthieu Sainlos9https://orcid.org/0000-0001-5465-5641Joris de Wit10Daniel Choquet11Olivier Thoumine12https://orcid.org/0000-0002-8041-1349University of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceVIB Center for Brain & Disease Research and KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven, BelgiumVIB Center for Brain & Disease Research and KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven, BelgiumUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceVIB Center for Brain & Disease Research and KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven, BelgiumUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, France; University of Bordeaux, CNRS UAR 3420, INSERM, Bordeaux Imaging Center, Bordeaux, FranceUniversity of Bordeaux, CNRS UMR 5297, Interdisciplinary Institute for Neuroscience, Bordeaux, FranceMDGA molecules can bind neuroligins and interfere with trans-synaptic interactions to neurexins, thereby impairing synapse development. However, the subcellular localization and dynamics of MDGAs, or their specific action mode in neurons remain unclear. Here, surface immunostaining of endogenous MDGAs and single molecule tracking of recombinant MDGAs in dissociated hippocampal neurons reveal that MDGAs are homogeneously distributed and exhibit fast membrane diffusion, with a small reduction in mobility across neuronal maturation. Knocking-down/out MDGAs using shRNAs and CRISPR/Cas9 strategies increases the density of excitatory synapses, the membrane confinement of neuroligin-1, and the phosphotyrosine level of neuroligins associated with excitatory post-synaptic differentiation. Finally, MDGA silencing reduces the mobility of AMPA receptors, increases the frequency of miniature EPSCs (but not IPSCs), and selectively enhances evoked AMPA-receptor-mediated EPSCs in CA1 pyramidal neurons. Overall, our results support a mechanism by which interactions between MDGAs and neuroligin-1 delays the assembly of functional excitatory synapses containing AMPA receptors.https://elifesciences.org/articles/75233synapse developmentadhesion moleculeshippocampal culturessingle molecule trackingElectrophysiology |
| spellingShingle | Andrea Toledo Mathieu Letellier Giorgia Bimbi Béatrice Tessier Sophie Daburon Alexandre Favereaux Ingrid Chamma Kristel Vennekens Jeroen Vanderlinden Matthieu Sainlos Joris de Wit Daniel Choquet Olivier Thoumine MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior eLife synapse development adhesion molecules hippocampal cultures single molecule tracking Electrophysiology |
| title | MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior |
| title_full | MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior |
| title_fullStr | MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior |
| title_full_unstemmed | MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior |
| title_short | MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior |
| title_sort | mdgas are fast diffusing molecules that delay excitatory synapse development by altering neuroligin behavior |
| topic | synapse development adhesion molecules hippocampal cultures single molecule tracking Electrophysiology |
| url | https://elifesciences.org/articles/75233 |
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