Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-D-Aspartate Receptor.
Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-D-Aspartate Receptor.
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由自身抗体引起的N-甲基-D-天冬氨酸受体引起的空间认知的选择性损害。
DOI：
10.1016/j.ebiom.2015.05.027
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发表时间：
2015-07
期刊：
影响因子：
11.1
通讯作者：
Diamond B
中科院分区：
文献类型：
--
作者：
Chang EH;Volpe BT;Mackay M;Aranow C;Watson P;Kowal C;Storbeck J;Mattis P;Berlin R;Chen H;Mader S;Huerta TS;Huerta PT;Diamond B
系统性红斑狼疮（SLE）患者在多个领域出现认知异常，包括处理速度、执行功能和记忆。在这里，我们表明，SLE患者携带的抗体，结合DNA和GluN 2A和GluN 2B亚基的N-甲基-D-天冬氨酸受体（NMDAR），称为DNRAbs，显示了选择性损害的空间回忆。在SLE的小鼠模型中，循环DNRAbs穿透海马的神经记录显示，CA 1位置细胞表现出位置场大小的显着扩张。结构分析表明，海马锥体细胞的树突状突起和棘大量减少。引人注目的是，当海马体中不再检测到DNRAb时，这些异常变得明显。这些结果表明，抗体介导的神经认知障碍可能是高度特异性的，空间认知可能特别容易受到DNRAB介导的海马细胞的结构和功能损伤，这些损伤在触发损伤不再存在后演变。具有NMDAR反应性抗体（DNRAb）的狼疮患者显示受损的空间记忆。DNRAb穿透海马的小鼠具有缺陷的CA 1位置细胞。暴露于DNRAb的CA 1和CA 3锥体细胞显示减少的树突状突起。DNRAb暴露引发锥体神经元的进行性损害。狼疮抗体的影响演变后，即使DNRAbs不再存在于大脑中。
Patients with systemic lupus erythematosus (SLE) experience cognitive abnormalities in multiple domains including processing speed, executive function, and memory. Here we show that SLE patients carrying antibodies that bind DNA and the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), termed DNRAbs, displayed a selective impairment in spatial recall. Neural recordings in a mouse model of SLE, in which circulating DNRAbs penetrate the hippocampus, revealed that CA1 place cells exhibited a significant expansion in place field size. Structural analysis showed that hippocampal pyramidal cells had substantial reductions in their dendritic processes and spines. Strikingly, these abnormalities became evident at a time when DNRAbs were no longer detectable in the hippocampus. These results suggest that antibody-mediated neurocognitive impairments may be highly specific, and that spatial cognition may be particularly vulnerable to DNRAb-mediated structural and functional injury to hippocampal cells that evolves after the triggering insult is no longer present. Lupus patients with NMDAR-reactive antibodies (DNRAbs) show impaired spatial memory. Mice in which DNRAbs penetrate the hippocampus have defective CA1 place cells. CA1 and CA3 pyramidal cells exposed to DNRAbs display reduced dendritic processes. DNRAb exposure initiates a progressive compromise in pyramidal neurons. Lupus antibody effects evolve even after DNRAbs are no longer present in the brain.