title: Tumor necrosis factor alpha mediates GABA(A) receptor trafficking to the plasma membrane of spinal cord neurons in vivo.
abstract: The proinflammatory cytokine TNFα contributes to cell death in central nervous system (CNS) disorders by altering synaptic neurotransmission. TNFα contributes to excitotoxicity by increasing GluA2-lacking AMPA receptor (AMPAR) trafficking to the neuronal plasma membrane. In vitro, increased AMPAR on the neuronal surface after TNFα exposure is associated with a rapid internalization of GABA(A) receptors (GABA(A)Rs), suggesting complex timing and dose dependency of the CNS's response to TNFα. However, the effect of TNFα on GABA(A)R trafficking in vivo remains unclear. We assessed the effect of TNFα nanoinjection on rapid GABA(A)R changes in rats (N = 30) using subcellular fractionation, quantitative western blotting, and confocal microscopy. GABA(A)R protein levels in membrane fractions of TNFα and vehicle-treated subjects were not significantly different by Western Blot, yet high-resolution quantitative confocal imaging revealed that TNFα induces GABA(A)R trafficking to synapses in a dose-dependent manner by 60 min. TNFα-mediated GABA(A)R trafficking represents a novel target for CNS excitotoxicity.
authors.affiliation: Brain and Spinal Injury Center-BASIC, Department of Neurological Surgery, University of California, San Francisco, CA 94110, USA.
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Stück
authors.forename: Randolph N
authors.initials: RN
authors.lastname: Christensen
authors.forename: J Russell
authors.initials: JR
authors.lastname: Huie
authors.forename: C Amy
authors.initials: CA
authors.lastname: Tovar
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Miller
authors.forename: Yvette S
authors.initials: YS
authors.lastname: Nout
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Bresnahan
authors.forename: Michael S
authors.initials: MS
authors.lastname: Beattie
authors.forename: Adam R
authors.initials: AR
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D011963:Receptors, GABA-A; D014409:Tumor Necrosis Factor-alpha