Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABA
ARs and cytosolic gephyrin aggregation

Zeppillo, Tommaso; Ali, Heba; Ravichandran, Sowbarnika; Ritter, Tamara C.; Wenger, Sally; López-Murcia, Francisco José; Gideons, Erinn; Signorelli, Janetti; Schmeisser, Michael J.; Wiltfang, Jens; Rhee, Jeong Seop; Brose, Nils; Taschenberger, Holger; Krüger-Burg, Dilja D.

doi:10.1038/s42003-024-06789-z

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Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABA_ARs and cytosolic gephyrin aggregation

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Zeppillo, Tommaso
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Ali, Heba
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Wenger, Sally
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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López-Murcia, Francisco José
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Signorelli, Janetti
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Rhee, Jeong Seop
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;
Research Group of Neurophysiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Brose, Nils
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Taschenberger, Holger
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Krüger-Burg, Dilja D.
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Zeppillo, T., Ali, H., Ravichandran, S., Ritter, T. C., Wenger, S., López-Murcia, F. J., et al. (2024). Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABA_ARs and cytosolic gephyrin aggregation. Communications Biology, 7: 1157. doi:10.1038/s42003-024-06789-z.

Cite as: https://hdl.handle.net/21.11116/0000-000F-DDC9-6

Abstract

Neuroligin-2 (Nlgn2) is a key synaptic adhesion protein at virtually all GABAergic synapses, which recruits GABAARs by promoting assembly of the postsynaptic gephyrin scaffold. Intriguingly, loss of Nlgn2 differentially affects subsets of GABAergic synapses, indicating that synapse-specific interactors and redundancies define its function, but the nature of these interactions remain poorly understood. Here we investigated how Nlgn2 function in hippocampal area CA1 is modulated by two proposed interaction partners, MDGA1 and MDGA2. We show that loss of MDGA1 expression, but not heterozygous deletion of MDGA2, ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behaviour characterizing Nlgn2 knockout (KO) mice. Additionally, combined Nlgn2 and MDGA1 deletion causes an exacerbated layer-specific loss of gephyrin puncta. Given that both Nlgn2 and the MDGA1 have been correlated with many psychiatric disorders, our data support the notion that cytosolic gephyrin aggregation may represent an interesting target for novel therapeutic strategies.