The proinflammatory cytokine tumor necrosis factor-␣ (TNF␣) 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␣ 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␣ 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 TNF␣ can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.