Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane.
Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane.
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DOI：
10.1523/jneurosci.3708-08.2008
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发表时间：
2008-10-29
期刊：
影响因子：
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通讯作者：
Beattie MS
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文献类型：
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作者：
Ferguson AR;Christensen RN;Gensel JC;Miller BA;Sun F;Beattie EC;Bresnahan JC;Beattie MS
谷氨酸是中枢神经系统中主要的兴奋性神经递质，参与正常的神经传递和兴奋性毒性。许多体外研究结果表明，离子型谷氨酸受体，AMPAR，可以迅速交通从细胞内商店到质膜，改变神经元的兴奋性。这些受体运输事件被认为与CNS可塑性以及学习和记忆有关。最近在体外研究中发现AMPAR的运输受促炎细胞因子肿瘤坏死因子α（TNFα）的神经胶质细胞释放的调节。这与几种CNS疾病具有潜在相关性，因为许多病理状态具有涉及TNFα的神经炎症组分。然而，TNFα诱导的AMPAR运输仅在原代或切片培养中进行了探索，尚未在CNS损伤的临床前模型中得到证实。在这里，我们使用共聚焦和图像分析技术来证明，脊髓损伤（SCI）诱导贩运的AMPAR神经元膜。然后，我们表明，这种作用是通过TNFα的纳米注射来模拟的，TNFα产生了GluR2缺乏受体的特异性运输，从而增强了兴奋性毒性。为了确定TNFα诱导的运输是否影响神经元细胞死亡，我们在SCI后使用可溶性TNFα受体隔离TNFα，并显著降低损伤半影区的AMPAR运输和神经元兴奋性毒性。这些数据首次提供了将TNFα诱导的AMPAR快速运输与体内CNS创伤后早期兴奋性毒性继发性损伤联系起来的证据，并证明了病理状态劫持参与正常突触可塑性的机制以产生细胞死亡的新方式。
Glutamate, the major excitatory neurotransmitter in the CNS, is implicated in both normal neurotransmission and excitotoxicity. Numerous in vitro findings indicate that the ionotropic glutamate receptor, AMPAR, can rapidly traffic from intracellular stores to the plasma membrane, altering neuronal excitability. These receptor trafficking events are thought to be involved in CNS plasticity as well as learning and memory. AMPAR trafficking has recently been shown to be regulated by glial release of the proinflammatory cytokine tumor necrosis factor α (TNFα) in vitro. This has potential relevance to several CNS disorders, because many pathological states have a neuroinflammatory component involving TNFα. However, TNFα-induced trafficking of AMPARs has only been explored in primary or slice cultures and has not been demonstrated in preclinical models of CNS damage. Here, we use confocal and image analysis techniques to demonstrate that spinal cord injury (SCI) induces trafficking of AMPARs to the neuronal membrane. We then show that this effect is mimicked by nanoinjections of TNFα, which produces specific trafficking of GluR2-lacking receptors which enhance excitotoxicity. To determine if TNFα-induced trafficking affects neuronal cell death, we sequestered TNFα after SCI using a soluble TNFα receptor, and significantly reduced both AMPAR trafficking and neuronal excitotoxicity in the injury penumbra. The data provide the first evidence linking rapid TNFα-induced AMPAR trafficking to early excitotoxic secondary injury after CNS trauma in vivo, and demonstrate a novel way in which pathological states hijack mechanisms involved in normal synaptic plasticity to produce cell death.