Tumor Necrosis Factor Alpha Mediates GABAAReceptor Trafficking to the Plasma Membrane of Spinal Cord NeuronsIn Vivo

[摘要] The proinflammatory cytokine TNFαcontributes to cell death in central nervous system (CNS) disorders by altering synaptic neurotransmission. TNFαcontributes to excitotoxicity by increasing GluA2-lacking AMPA receptor (AMPAR) trafficking to the neuronal plasma membrane.In vitro, increased AMPAR on the neuronal surface after TNFαexposure is associated with a rapid internalization of GABAAreceptors (GABAARs), suggesting complex timing and dose dependency of the CNS’s response to TNFα.However, the effect of TNFαon GABAAR traffickingin vivoremains unclear. We assessed the effect of TNFαnanoinjection on rapid GABAAR changes in rats (N=30) using subcellular fractionation, quantitative western blotting, and confocal microscopy. GABAAR protein levels in membrane fractions of TNFαand vehicle-treated subjects were not significantly different by Western Blot, yet high-resolution quantitative confocal imaging revealed that TNFαinduces GABAAR trafficking to synapses in a dose-dependent manner by 60 min. TNFα-mediated GABAAR trafficking represents a novel target for CNS excitotoxicity.

[学科分类] 精神健康和精神病学