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.

中文翻译：

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氯胺酮通过突触捕获减轻 NMDA 受体功能减退


N-甲基-D-天冬氨酸谷氨酸受体 （NMDAR） 在突触上的活动依赖性调节调节兴奋性神经传递并塑造认知功能。尽管 NMDAR 突触不稳定与严重的神经和精神疾病有关，但调整 NMDAR 突触捕获以评估其与治疗脑部疾病的临床相关性仍然是一个挑战。在这里，我们报道了氯胺酮 （KET） 和其他临床相关的 NMDAR 开放通道阻滞剂 （OCB） 促进 NMDAR 和包含 PDZ 结构域的支架蛋白之间的相互作用，并增强突触处的 NMDAR 捕获。我们进一步表明，KET 引发的捕获增强补偿了由抗 NMDAR 脑炎患者自身抗体触发的突触受体的耗竭。预防突触耗竭可减轻 NMDAR 介导的 CaMKII 信号传导损伤，并减轻自身抗体引起的焦虑和感觉运动门控相关行为缺陷。总而言之，这些发现揭示了 OCB 作用的意想不到的维度，并强调了在 NMDAR 相关突触病中靶向受体锚定的潜力。