Calcium-Permeable AMPA Receptors Are Expressed in a Rodent Model of Status Epilepticus
Calcium-Permeable AMPA Receptors Are Expressed in a Rodent Model of Status Epilepticus
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DOI：
10.1002/ana.23570
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发表时间：
2012-07-01
影响因子：
11.2
通讯作者：
Kapur, Jaideep
中科院分区：
文献类型：
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作者：
Rajasekaran, Karthik;Todorovic, Marko;Kapur, Jaideep
目标：方法：采用匹罗卡品诱发癫痫持续状态（SE），于首次5级发作后10min（难治性SE）和60min（迟发性SE）观察海马AMPA受体（AMPAR）介导的神经传递可塑性。用电压钳技术记录海马CA1区锥体神经元和齿状回颗粒细胞（DGCs）的AMPAR介导电流。用生物素化法测定海马膜GluA2亚基的表面表达。采用免疫细胞化学和活体成像技术研究了海马培养物中GluA2内化和细胞内钙（[Ca]（i））水平的变化。AMPAR拮抗剂治疗SE进行了评估，通过视频和脑电图。结果：AMPAR介导的电流记录从CA1神经元从难治性和晚期SE动物是向内整流，和philanthotoxin敏感;类似的变化观察到从DGCs从难治性SE动物的记录。GluA2亚基表面表达减少，在海马难治性和晚期SE。在培养的海马锥体神经元，反复爆发减少表面表达的GluA2亚基，提高其内化率。通过选择性抑制GluA2缺乏的AMPAR，可降低反复爆发诱导的[Ca]（i）水平升高。GYKI-52466终止了地西泮难治性SE。解释：在SE期间，AMPAR具有快速、持续的可塑性，表达GluA2缺乏的AMPAR。这些受体提供了Ca 2+进入主要神经元的另一个来源。苯二氮卓难治性SE可通过AMPAR拮抗作用终止。这些数据将AMPAR确定为治疗SE的潜在治疗靶点。神经网络2012; 72：91 - 102
Objective: A study was undertaken to characterize the plasticity of AMPA receptor (AMPAR)-mediated neurotransmission in the hippocampus during status epilepticus (SE).Methods: SE was induced by pilocarpine, and animals were studied 10 minutes (refractory SE) or 60 minutes (late SE) after the onset of the first grade 5 seizures. AMPAR-mediated currents were recorded from CA1 pyramidal neurons and dentate granule cells (DGCs) by voltage clamp technique. The surface expression of GluA2 subunit on hippocampal membranes was determined using a biotinylation assay. GluA2 internalization and changes in intracellular calcium ([Ca](i)) levels were studied in hippocampal cultures using immunocytochemical and live-imaging techniques. AMPAR antagonist treatment of SE was evaluated by video and electroencephalography.Results: AMPAR-mediated currents recorded from CA1 neurons from refractory and late SE animals were inwardly rectifying, and philanthotoxin-sensitive; similar changes were observed in recordings obtained from DGCs from refractory SE animals. GluA2 subunit surface expression was reduced in the hippocampus during refractory and late SE. In cultured hippocampal pyramidal neurons, recurrent bursting diminished surface expression of the GluA2 subunit and enhanced its internalization rate. Recurrent bursting-induced increase in [Ca](i) levels was reduced by selective inhibition of GluA2-lacking AMPARs. GYKI-52466 terminated diazepam-refractory SE.Interpretation: During SE, there is rapid, ongoing plasticity of AMPARs with the expression of GluA2-lacking AMPARs. These receptors provide another source of Ca2+ entry into the principal neurons. Benzodiazepam-refractory SE can be terminated by AMPAR antagonism. The data identify AMPARs as a potential therapeutic target for the treatment of SE. ANN NEUROL 2012;72:91-102