MDGAs Are Fast-diffusing Molecules That Delay Excitatory Synapse Development by Altering Neuroligin Behavior

Overview

Journal Elife

Specialty Biology

Date 2022 May 9

PMID 35532105

Authors

Andrea Toledo

Mathieu Letellier

Giorgia Bimbi

Beatrice Tessier

Sophie Daburon

Alexandre Favereaux

Ingrid Chamma

Kristel Vennekens

Jeroen Vanderlinden

Matthieu Sainlos

Joris de Wit

Daniel Choquet

Olivier Thoumine

Affiliations

Soon will be listed here.

Abstract

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.

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References

Trotter J, Hao J, Maxeiner S, Tsetsenis T, Liu Z, Zhuang X . Synaptic neurexin-1 assembles into dynamically regulated active zone nanoclusters. J Cell Biol. 2019; 218(8):2677-2698. PMC: 6683742. DOI: 10.1083/jcb.201812076. View

Dobin A, Davis C, Schlesinger F, Drenkow J, Zaleski C, Jha S . STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2012; 29(1):15-21. PMC: 3530905. DOI: 10.1093/bioinformatics/bts635. View

Bemben M, Shipman S, Hirai T, Herring B, Li Y, Badger 2nd J . CaMKII phosphorylation of neuroligin-1 regulates excitatory synapses. Nat Neurosci. 2013; 17(1):56-64. PMC: 3943352. DOI: 10.1038/nn.3601. View

Connor S, Ammendrup-Johnsen I, Kishimoto Y, Karimi Tari P, Cvetkovska V, Harada T . Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function. Cell Rep. 2017; 21(13):3637-3645. DOI: 10.1016/j.celrep.2017.11.109. View

Pettem K, Yokomaku D, Takahashi H, Ge Y, Craig A . Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development. J Cell Biol. 2013; 200(3):321-36. PMC: 3563690. DOI: 10.1083/jcb.201206028. View

Renner M, Choquet D, Triller A . Control of the postsynaptic membrane viscosity. J Neurosci. 2009; 29(9):2926-37. PMC: 6666215. DOI: 10.1523/JNEUROSCI.4445-08.2009. View

Gangwar S, Zhong X, Seshadrinathan S, Chen H, Machius M, Rudenko G . Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges. Neuron. 2017; 94(6):1132-1141.e4. PMC: 5745067. DOI: 10.1016/j.neuron.2017.06.009. View

Kerchner G, Nicoll R . Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci. 2008; 9(11):813-25. PMC: 2819160. DOI: 10.1038/nrn2501. View

Czondor K, Garcia M, Argento A, Constals A, Breillat C, Tessier B . Micropatterned substrates coated with neuronal adhesion molecules for high-content study of synapse formation. Nat Commun. 2013; 4:2252. DOI: 10.1038/ncomms3252. View

10.

Suzuki K, Hayashi Y, Nakahara S, Kumazaki H, Prox J, Horiuchi K . Activity-dependent proteolytic cleavage of neuroligin-1. Neuron. 2012; 76(2):410-22. DOI: 10.1016/j.neuron.2012.10.003. View

11.

Kwon H, Kozorovitskiy Y, Oh W, Peixoto R, Akhtar N, Saulnier J . Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number. Nat Neurosci. 2012; 15(12):1667-74. PMC: 3536444. DOI: 10.1038/nn.3256. View

12.

Bucan M, Abrahams B, Wang K, Glessner J, Herman E, Sonnenblick L . Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009; 5(6):e1000536. PMC: 2695001. DOI: 10.1371/journal.pgen.1000536. View

13.

Loh K, Stawski P, Draycott A, Udeshi N, Lehrman E, Wilton D . Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts. Cell. 2016; 166(5):1295-1307.e21. PMC: 5167540. DOI: 10.1016/j.cell.2016.07.041. View

14.

Elegheert J, Cvetkovska V, Clayton A, Heroven C, Vennekens K, Smukowski S . Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins. Neuron. 2017; 95(4):896-913.e10. PMC: 5563082. DOI: 10.1016/j.neuron.2017.07.040. View

15.

Kaech S, Banker G . Culturing hippocampal neurons. Nat Protoc. 2007; 1(5):2406-15. DOI: 10.1038/nprot.2006.356. View

16.

Lagardere M, Chamma I, Bouilhol E, Nikolski M, Thoumine O . FluoSim: simulator of single molecule dynamics for fluorescence live-cell and super-resolution imaging of membrane proteins. Sci Rep. 2020; 10(1):19954. PMC: 7672080. DOI: 10.1038/s41598-020-75814-y. View

17.

Sudhof T . Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits. Cell. 2017; 171(4):745-769. PMC: 5694349. DOI: 10.1016/j.cell.2017.10.024. View

18.

Cadwell C, Palasantza A, Jiang X, Berens P, Deng Q, Yilmaz M . Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat Biotechnol. 2015; 34(2):199-203. PMC: 4840019. DOI: 10.1038/nbt.3445. View

19.

Haas K, Compans B, Letellier M, Bartol T, Grillo-Bosch D, Sejnowski T . Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency. Elife. 2018; 7. PMC: 6070337. DOI: 10.7554/eLife.31755. View

20.

Irie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K . Binding of neuroligins to PSD-95. Science. 1997; 277(5331):1511-5. DOI: 10.1126/science.277.5331.1511. View