Rapid Tumor Necrosis Factor α-Induced Exocytosis of Glutamate Receptor 2-Lacking AMPA Receptors to Extrasynaptic Plasma Membrane Potentiates Excitotoxicity

The postinjury inflammatory response in the CNS leads to neuronal excitotoxicity. Our previous studies show that a major component of this response, the inflammatory cytokine tumor necrosis factor α (TNFα), causes a rapid increase in AMPA glutamate receptors (AMPARs) on the plasma membrane of cultured hippocampal neurons. This may potentiate neuron death through an increased vulnerability to AMPAR-dependent excitotoxic stress. Here, we test this hypothesis with an in vitro lactose dehydrogenase death assay and examine in detail the AMPAR surface delivery time course, receptor subtype, and synaptic and extrasynaptic distribution after TNFα exposure. These data demonstrate that surface levels of glutamate receptor 2 (GluR2)-lacking Ca2+-permeable AMPARs peak at 15 min after TNFα treatment, and the majority are directed to extrasynaptic sites. TNFα also induces an increase in GluR2-containing surface AMPARs but with a slower time course. We propose that this activity contributes to excitotoxic neuron death because TNFα potentiation of kainate excitotoxicity is blocked by a Ca2+-permeable AMPAR antagonist [NASPM (1-naphthyl acetyl spermine)] and a specific phosphoinositide 3 kinase (PI3 kinase) inhibitor (LY294,002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]) previously shown to block the TNFα-induced increase in AMPAR surface delivery. This information forms the basis for future in vivo studies examining AMPAR-dependent potentiation of excitotoxic neuron death and dysfunction caused by TNFα after acute injury and during neurodegenerative or neuropsychiatric disorders.

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