Cellular plasticity induced by anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis antibodies.
Cellular plasticity induced by anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis antibodies.
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DOI：
10.1002/ana.24293
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发表时间：
2015-03
影响因子：
11.2
通讯作者：
Balice-Gordon, Rita J.
中科院分区：
文献类型：
--
作者：
Peng, Xiaoyu;Hughes, Ethan G.;Moscato, Emilia H.;Parsons, Thomas D.;Dalmau, Josep;Balice-Gordon, Rita J.
自身免疫介导的抗α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）脑炎是一种严重但对治疗有反应的疾病，伴有明显的短期记忆丧失和癫痫发作。人们对患者抗体影响突触和神经元导致症状的机制知之甚少。用免疫染色、Western印迹和电生理学分析确定患者抗体对活大鼠海马神经元培养物的影响。我们表明，患者抗体导致选择性减少的总表面量和突触定位的GluA 1和GluA 2的AMPAR，无论受体亚基结合特异性，通过增加内化和降解的表面AMPAR集群。相反，患者抗体不改变兴奋性突触、N-甲基-D-天冬氨酸受体（NMDAR）簇或细胞活力的密度。针对细胞外表位的市售AMPAR抗体不导致表面和突触受体簇的损失，表明患者抗体的特异性作用。全细胞膜片钳记录的自发微型突触后电流显示，患者抗体减少AMPAR介导的电流，但不NMDAR介导的电流。有趣的是，神经元的几个功能特性也发生了改变：抑制性突触电流和囊泡γ-氨基丁酸转运体（vGAT）染色强度降低，而神经元的内在兴奋性和短间隔放电增加。这些结果证实，来自抗AMPAR脑炎患者的抗体选择性地消除表面和突触AMPAR，导致抑制性突触传递的稳态降低和内在兴奋性增加，这可能导致这种疾病患者中突出的记忆缺陷和癫痫。
Autoimmune-mediated anti–α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis is a severe but treatment-responsive disorder with prominent short-term memory loss and seizures. The mechanisms by which patient antibodies affect synapses and neurons leading to symptoms are poorly understood. The effects of patient antibodies on cultures of live rat hippocampal neurons were determined with immunostaining, Western blot, and electrophysiological analyses. We show that patient antibodies cause a selective decrease in the total surface amount and synaptic localization of GluA1- and GluA2-containing AMPARs, regardless of receptor subunit binding specificity, through increased internalization and degradation of surface AMPAR clusters. In contrast, patient antibodies do not alter the density of excitatory synapses, N-methyl-D-aspartate receptor (NMDAR) clusters, or cell viability. Commercially available AMPAR antibodies directed against extracellular epitopes do not result in a loss of surface and synaptic receptor clusters, suggesting specific effects of patient antibodies. Whole-cell patch clamp recordings of spontaneous miniature postsynaptic currents show that patient antibodies decrease AMPAR-mediated currents, but not NMDAR-mediated currents. Interestingly, several functional properties of neurons are also altered: inhibitory synaptic currents and vesicular γ-aminobutyric acid transporter (vGAT) staining intensity decrease, whereas the intrinsic excitability of neurons and short-interval firing increase. These results establish that antibodies from patients with anti-AMPAR encephalitis selectively eliminate surface and synaptic AMPARs, resulting in a homeostatic decrease in inhibitory synaptic transmission and increased intrinsic excitability, which may contribute to the memory deficits and epilepsy that are prominent in patients with this disorder.
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影响因子：
11.2
作者：
Lai, Meizan;Hughes, Ethan G.;Peng, Xiaoyu;Zhou, Lei;Gleichman, Amy J.;Shu, Huidy;Mata, Sabrina;Kremens, Daniel;Vitaliani, Roberta;Geschwind, Michael D.;Bataller, Luis;Kalb, Robert G.;Davis, Rebecca;Graus, Francesc;Lynch, David R.;Balice-Gordon, Rita;Dalmau, Josep
通讯作者：
Dalmau, Josep
影响因子：
5.3
作者：
Fernandez-Monreal, Monica;Brown, Tyler C.;Esteban, Jose A.
通讯作者：
Esteban, Jose A.
影响因子：
4.4
作者：
Chuntharapai, A;Dodge, K;Kim, KJ
通讯作者：
Kim, KJ
影响因子：
5.3
作者：
Kilman, V;van Rossum, MCW;Turrigiano, GG
通讯作者：
Turrigiano, GG
影响因子：
16.2
作者：
Ehlers, MD
通讯作者：
Ehlers, MD