Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.
Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.
复制标题
DOI：
10.1523/jneurosci.0167-10.2010
复制
发表时间：
2010-04-28
期刊：
影响因子：
--
通讯作者：
Balice-Gordon RJ
中科院分区：
文献类型：
--
作者：
Hughes EG;Peng X;Gleichman AJ;Lai M;Zhou L;Tsou R;Parsons TD;Lynch DR;Dalmau J;Balice-Gordon RJ
我们最近描述了一种严重的、潜在致命的、但治疗反应性的脑炎，这种脑炎与n -甲基- d -天冬氨酸受体（NMDAR）的自身抗体有关，并导致与NMDAR功能遗传或药理学衰减模型相似的行为症状。在这里，我们证明了患者的NMDAR抗体导致NMDAR表面密度和突触定位的选择性和可逆性降低，这与患者的抗体滴度相关。这种减少的机制是选择性抗体介导的表面NMDAR的capping和内化，因为从患者抗体制备的Fab片段并没有降低表面受体密度，但随后与抗Fab抗体交联再现了完整的患者NMDAR抗体引起的减少。此外，培养的大鼠海马神经元的微型兴奋性突触后电流的全细胞膜片钳记录显示，患者的抗体特异性地降低了突触nmdar介导的电流，而不影响AMPA受体介导的电流。与这些对NMDARs的深刻影响相反，患者的抗体不会改变其他谷氨酸受体或突触蛋白的定位或表达、突触数量、树突棘、树突复杂性或细胞存活。此外，注入患者抗体的雌性Lewis大鼠海马NMDAR密度显著降低，与尸检患者海马NMDAR密度降低相似。这些研究确立了抗nmdar脑炎患者的抗体导致特异性、滴度依赖性和可逆性NMDARs丧失的细胞机制。这种谷氨酸受体亚型的丧失消除了nmdar介导的突触功能，导致在抗nmdar脑炎患者中观察到的学习、记忆和其他行为缺陷。
We recently described a severe, potentially lethal, but treatment responsive encephalitis that associates with autoantibodies to the N-methyl-D-aspartate receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibody mediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface receptor density, but subsequent crosslinking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch clamp recordings of miniature excitatory postsynaptic currents in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate receptors eliminates NMDAR-mediated synaptic function resulting in the learning, memory and other behavioral deficits observed in patients with anti-NMDAR encephalitis.