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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 C; Yagensky, Oleksandr; Krueger-Burg, Dilja; Hammer, Matthieu; Hsiao, He-Hsuan; Laskowski, Pawel R; Dyck, Lydia; Puche, Adam C; Sassoè-Pognetto, Marco; Chua, John J E; Urlaub, Henning; Jahn, Olaf; Brose, Nils; Poulopoulos, Alexandros.
Affiliation
  • Altas B; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Tuffy LP; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Patrizi A; Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.
  • Dimova K; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Neuroproteomics Group, Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Soykan T; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Brandenburg C; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Romanowski AJ; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Whitten JR; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Robertson CD; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Khim SN; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Crutcher GW; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Ambrozkiewicz MC; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Yagensky O; Research Group Protein Trafficking in Synaptic Development and Function, Laboratory of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Krueger-Burg D; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Hammer M; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Hsiao HH; Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Laskowski PR; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Dyck L; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Puche AC; Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Sassoè-Pognetto M; Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.
  • Chua JJE; Research Group Protein Trafficking in Synaptic Development and Function, Laboratory of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Urlaub H; Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Bioanalytics Group, Institute of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
  • Jahn O; Neuroproteomics Group, Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Translational Neuroproteomics Group, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
  • Brose N; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • Poulopoulos A; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany. Electronic address: apoulopoulos@som.umaryland.edu.
Biol Psychiatry ; 2023 Dec 27.
Article in En | MEDLINE | ID: mdl-38154503
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 (clustered regularly interspaced short palindromic repeats/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.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Biol Psychiatry Year: 2023 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Biol Psychiatry Year: 2023 Document type: Article Country of publication: United States