Region-Specific Phosphorylation Determines Neuroligin-3 Localization to 
Excitatory versus Inhibitory Synapses

Altas, Bekir; Tuffy, Liam P.; Patrizi, Annarita; Dimova, Kalina; Soykan, Tolga; Brandenburg, Cheryl; Romanowski, Andrea J.; Whitten, Julia R.; Robertson, Colin D.; Khim, Saovleak N.; Crutcher, Garrett W.; Ambrozkiewicz, Mateusz; Yagensky, Oleksandr; Krüger-Burg, Dilja D.; Hammer, Matthieu; Hsiao, He-Hsuan; Laskowski, Pawel R.; Dyck, Lydia; Puche, Adam C.; Sassoè-Pognetto, Marco; Chua, J. J. E.; Urlaub, Henning; Jahn, Olaf; Brose, Nils; Poulopoulos, Alexandros

doi:10.1016/j.biopsych.2023.12.020

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Region-Specific Phosphorylation Determines Neuroligin-3 Localization to Excitatory versus Inhibitory Synapses

MPS-Authors

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Tuffy, Liam P.
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons14989

Dimova, Kalina
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182419

Soykan, Tolga
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182069

Ambrozkiewicz, Mateusz
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons191725

Yagensky, Oleksandr
Emeritus Group Laboratory of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182261

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

/persons/resource/persons182177

Hammer, Matthieu
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons15253

Hsiao, He-Hsuan
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons295147

Laskowski, Pawel R.
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons295149

Dyck, Lydia
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons14947

Chua, J. J. E.
Emeritus Group Laboratory of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons15947

Urlaub, Henning
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182214

Jahn, Olaf
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

/persons/resource/persons182104

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

/persons/resource/persons182355

Poulopoulos, Alexandros
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Altas, B., Tuffy, L. P., Patrizi, A., Dimova, K., Soykan, T., Brandenburg, C., et al. (2023). Region-Specific Phosphorylation Determines Neuroligin-3 Localization to Excitatory versus Inhibitory Synapses. Biological Psychiatry, in press. doi:10.1016/j.biopsych.2023.12.020.

Cite as: https://hdl.handle.net/21.11116/0000-000E-43FC-B

Abstract

Background:
Neuroligin-3 is a postsynaptic adhesion molecule involved in synapse development and function. It is implicated in rare, monogenic forms of autism, and its shedding is critical to the tumor microenvironment of gliomas. While other members of the Neuroligin family exhibit synapse-type specificity in localization and function through distinct interactions with postsynaptic scaffold proteins, the specificity of Neuroligin-3 synaptic localization remains largely unknown.

Methods:
We investigated the synaptic localization of Neuroligin-3 across regions in mouse and human brain samples after validating antibody specificity in knockout animals. We raised a phospho-specific Neuroligin antibody and used phosphoproteomics, cell-based assays, and in utero CRISPR/Cas9 knockout and gene replacement to identify mechanisms that regulate Neuroligin-3 localization to distinct synapse types.

Results:
Neuroligin-3 exhibits region-dependent synapse specificity, largely localizing to excitatory synapses in cortical regions and inhibitory synapses in subcortical regions of the brain in both mice and humans. We identified specific phosphorylation of cortical Neuroligin-3 at a key binding site for recruitment to inhibitory synapses, while subcortical Neuroligin-3 remained unphosphorylated. In vitro, phosphomimetic mutation of that site disrupted Neuroligin-3 association with the inhibitory postsynaptic scaffolding protein, Gephyrin. In vivo, phosphomimetic mutants of Neuroligin-3 localized to excitatory postsynapses, while phospho-null mutants localized to inhibitory postsynapses.

Conclusions:
These data reveal an unexpected region-specific pattern of Neuroligin-3 synapse specificity, as well as a phosphorylation-dependent mechanism that regulates its recruitment to either excitatory or inhibitory synapses. These findings add to our understanding of how Neuroligin-3 is involved in conditions that may affect the balance of excitation and inhibition.