Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha.
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.
Stellwagen
David
D
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford Medical School, Palo Alto, California 94305, USA.
Beattie
Eric C
EC
Seo
Jae Y
JY
Malenka
Robert C
RC
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D019921:Biotinylation / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000906:Antibodies; D004791:Enzyme Inhibitors; D018091:Receptors, AMPA; D018079:Receptors, GABA; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha