Ketamine alleviates NMDA receptor hypofunction through synaptic trapping.
Neuron
; 112(19): 3311-3328.e9, 2024 Oct 09.
Article
en En
| MEDLINE
| ID: mdl-39047728
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autoanticuerpos
/
Sinapsis
/
Receptores de N-Metil-D-Aspartato
/
Ketamina
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Neuron
Asunto de la revista:
NEUROLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos