Human Autoantibodies Against N-Methyl-D-Aspartate Receptor Modestly Alter Dopamine D1 Receptor Surface Dynamics.

Hélène Gréa, Delphine Bouchet, Véronique Rogemond, Nora Hamdani, Emmanuel Le Guen, Ryad Tamouza, Estelle Darrau, Christine Passerieux, Jérôme Honnorat, Marion Leboyer, Laurent Groc
Front. Psychiatry. 2019-09-13; 10:
DOI: 10.3389/fpsyt.2019.00670

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https://www.bordeaux-neurocampus.fr/12290

Gréa H(1)(2), Bouchet D(1)(2), Rogemond V(3)(4)(5), Hamdani N(6)(7)(8)(9), Le Guen E(6)(7)(8)(9), Tamouza R(6)(7)(8)(9), Darrau E(7), Passerieux C(9)(10)(11), Honnorat J(3)(4)(5), Leboyer M(6)(7)(8)(9), Groc L(1)(2).

Author information:
(1)Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR
5297, Bordeaux, France.
(2)CNRS, IINS UMR 5297, Bordeaux, France.
(3)NeuroMyoGene Institute, INSERM U1217/CNRS UMR 5310, Lyon, France.
(4)French Reference Center of Paraneoplastic Neurological Syndrome, Hospices
Civils de Lyon, Hôpital Neurologique, Lyon, France.
(5)Université de Lyon – Université Claude Bernard Lyon 1, Lyon, France.
(6)Université Paris Est Créteil, Psychiatry Department, Groupe Hospitalier
Universitaire Henri Mondor, AP-HP, DHU PePSY, Créteil, France.
(7)Université Paris Est Créteil, Life Science and Health Department, INSERM IMRB
U955, Créteil, France.
(8)INSERM, IMRB U955, Translational Psychiatry laboratory, Créteil, France.
(9)FondaMental foundation, Créteil, France.
(10)Université de Versaillles Saint Quentin en Yvelines, HandiRESP laboratory
(EA4047), Health Science Department Simone Veil, Montigny le Bretonneux, France.
(11)Versailles Hospital, Department of Adult Psychiatry, Le Chesnay, France.

Circulating autoantibodies directed against extracellular domains of the
glutamatergic N-methyl-D-aspartate receptors (NMDAR-Ab) elicit psychotic
symptoms in humans and behavioral deficits in animal models. Recent advances
suggest that NMDAR-Ab exert their pathogenic action by altering the trafficking
of NMDAR, which results in a synaptic NMDAR hypofunction consistent with the
consensual glutamatergic hypothesis of psychotic disorders. Yet, dysfunction in
the dopaminergic signaling is also proposed to be at the core of psychotic
disorders. Since NMDAR and dopamine D1 receptors (D1R) form membrane signaling
complexes, we investigated whether NMDAR-Ab purified from patients with
NMDAR-encephalitis or schizophrenia impaired D1R surface dynamics. As previous
data demonstrated that NMDAR-Ab, at least from NMDAR-encephalitis patients,
mainly bind to hippocampal NMDAR, we used single nanoparticle imaging to track
D1R specifically at the surface of hippocampal neurons that were exposed to
either purified G type immunoglobulins (IgGs) from NMDAR-Ab seropositive
patients suffering from NMDAR-encephalitis or schizophrenia, or control IgGs
from healthy NMDAR-Ab seropositive or seronegative subjects. We report that
overnight incubation with NMDAR-Ab from patients, but not from healthy carriers,
decreased the surface dynamics of D1R compared with NMDAR-Ab seronegative IgGs.
This decrease was abolished, and even reversed, in D1R mutant that cannot
physically interact with NMDAR. Overall, our data indicate that NMDAR-Ab from
patients with psychotic symptoms alter the trafficking of D1R, likely through
the surface crosstalk between NMDAR and D1R.