Achucarro Basque Center for Neuroscience, Biomedical Research Networking Center on Neurodegenerative Diseases and Department of Neurosciences, University of the Basque Country, Leioa, Spain.
August Pi i Sunyer Biomedical Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Ann Neurol. 2020 May;87(5):670-676. doi: 10.1002/ana.25699. Epub 2020 Feb 24.
Antibodies against neuronal N-methyl-D-aspartate receptors (NMDARs) in patients with anti-NMDAR encephalitis alter neuronal synaptic function and plasticity, but the effects on other cells of the nervous system are unknown.
Cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis (preabsorbed or not with GluN1) and a human NMDAR-specific monoclonal antibody (SSM5) derived from plasma cells of a patient, along the corresponding controls, were used in the studies. To evaluate the activity of oligodendrocyte NMDARs and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in vitro after exposure to patients' CSF antibodies or SSM5, we used a functional assay based on cytosolic Ca imaging. Expression of the glucose transporter (GLUT1) in oligodendrocytes was assessed by immunocytochemistry.
NMDAR agonist responses were robustly reduced after preincubation of oligodendrocytes with patients' CSF or SSM5 but remained largely unaltered with the corresponding controls. These effects were NMDAR specific, as patients' CSF did not alter responses to AMPA receptor agonists and was abrogated by preabsorption of CSF with HEK cells expressing GluN1 subunit. Patients' CSF also reduced oligodendrocyte expression of glucose transporter GLUT1 induced by NMDAR activity.
Antibodies from patients with anti-NMDAR encephalitis specifically alter the function of NMDARs in oligodendrocytes, causing a decrease of expression of GLUT1. Considering that normal GLUT1 expression in oligodendrocytes and myelin is needed to metabolically support axonal function, the findings suggest a link between antibody-mediated dysfunction of NMDARs in oligodendrocytes and the white matter alterations reported in patients with this disorder. ANN NEUROL 2020;87:670-676.
抗 N-甲基-D-天冬氨酸受体（NMDAR）抗体在抗 NMDAR 脑炎患者中改变神经元突触功能和可塑性，但对神经系统其他细胞的影响尚不清楚。
使用抗 NMDAR 脑炎患者的脑脊液（CSF）（预吸附或不预吸附 GluN1）和源自患者浆细胞的人 NMDAR 特异性单克隆抗体（SSM5），以及相应的对照，进行体外研究。为了评估暴露于患者 CSF 抗体或 SSM5 后体外少突胶质细胞 NMDAR 和 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的活性，我们使用了基于细胞溶质 Ca 成像的功能测定。通过免疫细胞化学评估少突胶质细胞中葡萄糖转运蛋白（GLUT1）的表达。
在用患者 CSF 或 SSM5 预孵育后，少突胶质细胞的 NMDAR 激动剂反应明显降低，但与相应的对照相比基本保持不变。这些作用是 NMDAR 特异性的，因为患者的 CSF 不会改变对 AMPA 受体激动剂的反应，并且通过用表达 GluN1 亚基的 HEK 细胞预吸附 CSF 而被阻断。患者 CSF 还降低了 NMDAR 活性诱导的少突胶质细胞葡萄糖转运蛋白 GLUT1 的表达。
来自抗 NMDAR 脑炎患者的抗体特异性改变少突胶质细胞中 NMDAR 的功能，导致 GLUT1 的表达减少。考虑到少突胶质细胞和髓鞘中正常的 GLUT1 表达对于代谢支持轴突功能是必需的，这些发现表明抗 NMDAR 抗体在少突胶质细胞中的功能障碍与该疾病患者报告的白质改变之间存在联系。神经病学年鉴 2020；87：670-676。
