Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-α

The proinflammatory cytokine tumor necrosis factor-alpha (TNF alpha) 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 TNF alpha 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, TNF alpha causes an endocytosis of GABA(A) receptors, resulting in fewer surface GABAA receptors and a decrease in inhibitory synaptic strength. These results suggest that TNF alpha can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.