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Immuno-Pharmacological Characterization of Presynaptic GluN3A-Containing NMDA Autoreceptors: Relevance to Anti-NMDA Receptor Autoimmune Diseases

  • Guendalina Olivero
  • Matteo Vergassola
  • Francesca Cisani
  • Cesare Usai
  • Anna PittalugaEmail author
Article
  • 27 Downloads

Abstract

Mouse hippocampal glutamatergic nerve endings express presynaptic release-regulating NMDA autoreceptors (NMDARs). The presence of GluN1, GluN2A, GluN2B, and GluN3A subunits in hippocampal vesicular glutamate transporter type 1-positive synaptosomes was confirmed with confocal microscopy. GluN2C, GluN2D, and GluN3B immunopositivity was scarcely present. Incubation of synaptosomes with the anti-GluN1, the anti-GluN2A, the anti-GluN2B, or the anti-GluN3A antibody prevented the 30 μM NMDA/1 μM glycine-evoked [3H]d-aspartate ([3H]d-ASP) release. The NMDA/glycine-evoked [3H]d-ASP release was reduced by increasing the external protons, consistent with the participation of GluN1 subunits lacking the N1 cassette to the receptor assembly. The result also excludes the involvement of GluN1/GluN3A dimers into the NMDA-evoked overflow. Complement (1:300) released [3H]d-ASP in a dizocilpine-sensitive manner, suggesting the participation of a NMDAR-mediated component in the releasing activity. Accordingly, the complement-evoked glutamate overflow was reduced in anti-GluN-treated synaptosomes when compared to the control. We speculated that incubation with antibodies had favored the internalization of NMDA receptors. Indeed, a significant reduction of the GluN1 and GluN2B proteins in the plasma membranes of anti-GluN1 or anti-GluN2B antibody-treated synaptosomes emerged in biotinylation studies. Altogether, our findings confirm the existence of presynaptic GluN3A-containing release-regulating NMDARs in mouse hippocampal glutamatergic nerve endings. Furthermore, they unveil presynaptic alteration of the GluN subunit insertion in synaptosomal plasma membranes elicited by anti-GluN antibodies that might be relevant to the central alterations occurring in patients suffering from autoimmune anti-NMDA diseases.

Keywords

Presynaptic NMDA autoreceptor GluN3 Anti-GluN antibody Complement NMDA internalization 

Notes

Acknowledgements

The authors thank Maura Agate and Silvia Smith, PhD (University of Utah, School of Medicine) for editorial assistance and Prof. Alberto Diaspro for the confocal microscope availability at the Department of Physics, University of Genova.

Funding Information

This work was supported by the University of Genoa (Fondi per la Ricerca di Ateneo).

Compliance with Ethical Standard

The experimental procedures were in accordance with the European legislation (European Communities Council Directive of 24 November 1986, 86/609/EEC) and the ARRIVE guidelines, and they were approved by the Italian Ministry of Health (DDL 26/2014 and previous legislation; protocol number no. 50/2011-B).

Conflict of Interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. 1.Department of Pharmacy, DiFAR, Pharmacology and Toxicology SectionUniversity of GenoaGenoaItaly
  2. 2. Institute of Biophysics, National Research CouncilGenoaItaly
  3. 3.IRCCS Ospedale Policlinico San MartinoGenovaItaly

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