NMDA受体
神经科学
氯胺酮
心理学
受体
医学
内科学
作者
Frédéric Villega,Alexandra R. Fernandes,Julie Jézéquel,Floriane Uyttersprot,Nathan Bénac,Sarra Zenagui,Laurine Bastardo,Hélène Gréa,Delphine Bouchet,Léa Villetelle,Olivier Nicole,Véronique Rogemond,Jérôme Honnorat,Julien P. Dupuis,Laurent Groc
出处
期刊:Neuron
[Elsevier]
日期:2024-07-01
标识
DOI:10.1016/j.neuron.2024.06.028
摘要
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.
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