Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling

Cell. 2015 Dec 17;163(7):1730-41. doi: 10.1016/j.cell.2015.11.023. Epub 2015 Dec 10.


The occurrence of cognitive disturbances upon CNS inflammation or infection has been correlated with increased levels of the cytokine tumor necrosis factor-α (TNFα). To date, however, no specific mechanism via which this cytokine could alter cognitive circuits has been demonstrated. Here, we show that local increase of TNFα in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 (TNFR1), which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses. Astrocytic TNFR1 signaling is necessary for the hippocampal synaptic alteration and contextual learning-memory impairment observed in experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS). This process may contribute to the pathogenesis of cognitive disturbances in MS, as well as in other CNS conditions accompanied by inflammatory states or infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Dentate Gyrus / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology*
  • Humans
  • Learning
  • Memory*
  • Mice
  • Multiple Sclerosis / physiopathology
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • ifenprodil