Ketamine alleviates NMDA receptor hypofunction through synaptic trapping

Frédéric Villéga, Alexandra Fernandes, Julie Jézéquel, Floriane Uyttersprot, Nathan Benac, Sarra Zenagui, Laurine Bastardo, Hélène Gréa, Delphine Bouchet, Léa Villetelle, Olivier Nicole, Véronique Rogemond, Jérôme Honnorat, Julien P. Dupuis, Laurent Groc
Neuron. 2024-10-01; 112(19): 3311-3328.e9
DOI: 10.1016/j.neuron.2024.06.028

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Villéga F(1), Fernandes A(2), Jézéquel J(2), Uyttersprot F(2), Benac N(2),
Zenagui S(2), Bastardo L(2), Gréa H(2), Bouchet D(2), Villetelle L(2), Nicole
O(2), Rogemond V(3), Honnorat J(3), Dupuis JP(4), Groc L(5).

Author information:
(1)University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience,
IINS UMR 5297, 33000 Bordeaux, France; Department of Pediatric Neurology,
CIC-1401, University Children’s Hospital of Bordeaux, Bordeaux, France.
(2)University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience,
IINS UMR 5297, 33000 Bordeaux, France.
(3)Synaptopathies and Autoantibodies Team, Institut NeuroMyoGene-MeLis, INSERM
U1314, CNRS UMR 5284, Université Claude Bernard Lyon1, 69373 Lyon, France;
French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune
Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer,
69677 Bron, France.
(4)University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience,
IINS UMR 5297, 33000 Bordeaux, France. Electronic address:
.
(5)University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience,
IINS UMR 5297, 33000 Bordeaux, France. Electronic address:
.

Activity-dependent modulations of N-methyl-D-aspartate glutamate receptor
(NMDAR) trapping at synapses regulate excitatory neurotransmission and shape
cognitive functions. Although NMDAR synaptic destabilization has been associated
with severe neurological and psychiatric conditions, tuning NMDAR synaptic
trapping to assess its clinical relevance for the treatment of brain conditions
remains a challenge. Here, we report that ketamine (KET) and other clinically
relevant NMDAR open channel blockers (OCBs) promote interactions between NMDAR
and PDZ-domain-containing scaffolding proteins and enhance NMDAR trapping at
synapses. We further show that KET-elicited trapping enhancement compensates for
depletion in synaptic receptors triggered by autoantibodies from patients with
anti-NMDAR encephalitis. Preventing synaptic depletion mitigates impairments in
NMDAR-mediated CaMKII signaling and alleviates anxiety- and
sensorimotor-gating-related behavioral deficits provoked by autoantibodies.
Altogether, these findings reveal an unexpected dimension of OCB action and
stress the potential of targeting receptor anchoring in NMDAR-related
synaptopathies.