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Alteration of NMDA receptor trafficking as a cellular hallmark of psychosis
Translational Psychiatry ( IF 5.8 ) Pub Date : 2021-08-30 , DOI: 10.1038/s41398-021-01549-7
Agnès Espana 1 , Henrik Seth 2 , Julie Jézéquel 1 , Tingting Huang 1 , Delphine Bouchet 1 , Marylin Lepleux 1 , Hélène Gréa 1 , Karl Bechter 3 , Marion Schneider 4 , Eric Hanse 2 , Laurent Groc 1, 2
Affiliation  

A dysfunction of the glutamatergic transmission, especially of the NMDA receptor (NMDAR), constitutes one of the main biological substrate of psychotic disorders, such as schizophrenia. The NMDAR signaling hypofunction, through genetic and/or environmental insults, would cause a neurodevelopmental myriad of molecular, cellular, and network alterations that persist throughout life. Yet, the mechanisms underpinning NMDAR dysfunctions remain elusive. Here, we compared the membrane trafficking of NMDAR in three gold-standard models of schizophrenia, i.e., patient’s cerebrospinal fluids, genetic manipulations of susceptibility genes, and prenatal developmental alterations. Using a combination of single nanoparticle tracking, electrophysiological, biochemical, and behavioral approaches in rodents, we identified that the NMDAR trafficking in hippocampal neurons was consistently altered in all these different models. Artificial manipulations of the NMDAR surface dynamics with competing ligands or antibody-induced receptor cross-link in the developing rat brain were sufficient to regulate the adult acoustic startle reflex and compensate for an early pathological challenge. Collectively, we show that the NMDAR trafficking is markedly altered in all clinically relevant models of psychosis, opening new avenues of therapeutical strategies.



中文翻译:

NMDA 受体贩运的改变是精神病的细胞标志

谷氨酸能传递的功能障碍,尤其是 NMDA 受体 (NMDAR) 的功能障碍,构成了精神障碍(例如精神分裂症)的主要生物学底物之一。NMDAR 信号传导功能减退,通过遗传和/或环境损伤,会导致神经发育无数的分子、细胞和网络改变,这些改变会持续一生。然而,支撑 NMDAR 功能障碍的机制仍然难以捉摸。在这里,我们比较了三种精神分裂症黄金标准模型中 NMDAR 的膜运输,即患者的脑脊液、易感基因的遗传操作和产前发育改变。在啮齿类动物中结合使用单个纳米粒子追踪、电生理学、生化和行为方法,我们发现在所有这些不同的模型中,海马神经元中的 NMDAR 运输一直在改变。在发育中的大鼠大脑中,用竞争配体或抗体诱导的受体交联对 NMDAR 表面动力学进行人工操作,足以调节成人听觉惊跳反射并补偿早期病理挑战。总的来说,我们表明 NMDAR 贩运在所有临床相关的精神病模型中都发生了显着改变,开辟了治疗策略的新途径。在发育中的大鼠大脑中,用竞争配体或抗体诱导的受体交联对 NMDAR 表面动力学进行人工操作,足以调节成人的听觉惊跳反射并补偿早期的病理挑战。总的来说,我们表明 NMDAR 贩运在所有临床相关的精神病模型中都发生了显着改变,开辟了治疗策略的新途径。在发育中的大鼠大脑中,用竞争配体或抗体诱导的受体交联对 NMDAR 表面动力学进行人工操作,足以调节成人的听觉惊跳反射并补偿早期的病理挑战。总的来说,我们表明 NMDAR 贩运在所有临床相关的精神病模型中都发生了显着改变,开辟了治疗策略的新途径。

更新日期:2021-08-30
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