The proinflammatory cytokine tumor necrosis factor-α (TNFα) has been shown to rapidly exocytose AMPA receptors in hippocampal pyramidal cells and is essential for maintaining normal surface expression of these receptors. This study demonstrates that TNFα acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase (PI3K)-dependent process, increasing excitatory synaptic strength while altering the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFα causes endocytosis of GABA_A receptors, leading to fewer surface GABA_A receptors and a decrease in inhibitory synaptic strength. These findings suggest that TNFα can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults. The study also highlights the unique role of TNFα in regulating neurotransmitter receptor trafficking and its potential implications for neuropathology.The proinflammatory cytokine tumor necrosis factor-α (TNFα) has been shown to rapidly exocytose AMPA receptors in hippocampal pyramidal cells and is essential for maintaining normal surface expression of these receptors. This study demonstrates that TNFα acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase (PI3K)-dependent process, increasing excitatory synaptic strength while altering the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFα causes endocytosis of GABA_A receptors, leading to fewer surface GABA_A receptors and a decrease in inhibitory synaptic strength. These findings suggest that TNFα can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults. The study also highlights the unique role of TNFα in regulating neurotransmitter receptor trafficking and its potential implications for neuropathology.