Allosteric nanobodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual fear consolidation

Pauline Scholler, Damien Nevoltris, Dimitri de Bundel, Simon Bossi, David Moreno-Delgado, Xavier Rovira, Thor C. Møller, Driss El Moustaine, Michaël Mathieu, Emilie Blanc, Heather McLean, Elodie Dupuis, Gérard Mathis, Eric Trinquet, Hervé Daniel, Emmanuel Valjent, Daniel Baty, Patrick Chames (), Philippe Rondard () and Jean-Philippe Pin ()
Additional contact information
Pauline Scholler: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Damien Nevoltris: Cisbio Bioassays
Dimitri de Bundel: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Simon Bossi: CNRS UMR9197, Université Paris-Sud, Institut des Neurosciences Paris-Saclay
David Moreno-Delgado: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Xavier Rovira: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Thor C. Møller: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Driss El Moustaine: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Michaël Mathieu: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Emilie Blanc: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Heather McLean: CNRS UMR9197, Université Paris-Sud, Institut des Neurosciences Paris-Saclay
Elodie Dupuis: Cisbio Bioassays
Gérard Mathis: Cisbio Bioassays
Eric Trinquet: Cisbio Bioassays
Hervé Daniel: CNRS UMR9197, Université Paris-Sud, Institut des Neurosciences Paris-Saclay
Emmanuel Valjent: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Daniel Baty: Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM
Patrick Chames: Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM
Philippe Rondard: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier
Jean-Philippe Pin: Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Antibodies have enormous therapeutic and biotechnology potential. G protein-coupled receptors (GPCRs), the main targets in drug development, are of major interest in antibody development programs. Metabotropic glutamate receptors are dimeric GPCRs that can control synaptic activity in a multitude of ways. Here we identify llama nanobodies that specifically recognize mGlu2 receptors, among the eight subtypes of mGluR subunits. Among these nanobodies, DN10 and 13 are positive allosteric modulators (PAM) on homodimeric mGlu2, while DN10 displays also a significant partial agonist activity. DN10 and DN13 have no effect on mGlu2-3 and mGlu2-4 heterodimers. These PAMs enhance the inhibitory action of the orthosteric mGlu2/mGlu3 agonist, DCG-IV, at mossy fiber terminals in the CA3 region of hippocampal slices. DN13 also impairs contextual fear memory when injected in the CA3 region of hippocampal region. These data highlight the potential of developing antibodies with allosteric actions on GPCRs to better define their roles in vivo.

Date: 2017
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DOI: 10.1038/s41467-017-01489-1

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