Stellwagen David, Beattie Eric C, Seo Jae Y, Malenka Robert C
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford Medical School, Palo Alto, California 94305, USA.
J Neurosci. 2005 Mar 23;25(12):3219-28. doi: 10.1523/JNEUROSCI.4486-04.2005.
The proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of normal surface expression of AMPA receptors. Here we demonstrate that TNFalpha acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFalpha causes an endocytosis of GABA(A) receptors, resulting in fewer surface GABA(A) receptors and a decrease in inhibitory synaptic strength. These results suggest that TNFalpha can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.
促炎细胞因子肿瘤坏死因子-α（TNFα）可导致海马锥体细胞中AMPA受体迅速胞吐，并且是维持AMPA受体正常表面表达所必需的。在此，我们证明TNFα作用于神经元TNFR1受体，通过磷脂酰肌醇3激酶依赖性过程优先使缺乏谷氨酸受体2的AMPA受体胞吐。这增加了兴奋性突触强度，同时改变了突触AMPA受体的分子化学计量。相反，TNFα导致GABA(A)受体的内吞作用，导致表面GABA(A)受体减少，抑制性突触强度降低。这些结果表明，TNFα可以调节神经元回路的稳态，其方式可能会加剧神经元损伤导致的兴奋性毒性损伤。
