Tumor Necrosis Factor Alpha Mediates GABAA Receptor Trafficking to the Plasma Membrane of Spinal Cord Neurons In Vivo

The proinflammatory cytokine TNF alpha contributes to cell death in central nervous system (CNS) disorders by altering synaptic neurotransmission. TNF alpha 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 TNF alpha 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 TNF alpha. However, the effect of TNF alpha on GABA(A)R trafficking in vivo remains unclear. We assessed the effect of TNF alpha 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 TNF alpha and vehicle-treated subjects were not significantly different by Western Blot, yet high-resolution quantitative confocal imaging revealed that TNF alpha induces GABA(A)R trafficking to synapses in a dose-dependent manner by 60 min. TNF alpha-mediated GABA(A)R trafficking represents a novel target for CNS excitotoxicity.