Memory you forget


Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling

Samia Habbas, Mirko Santello, Denise Becker, Hiltrud Stubbe, Giovanna Zappia, Nicolas Liaudet,
Federica R. Klaus, George Kollias, Adriano Fontana, Christopher R. Pryce, Tobias Suter, Andrea Volterra


Volume 163, Issue 7, 17 December 2015, Pages 1730–1741


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.

    Figure: Mice with EAE display impairment of long-term contextual memory, this is linked to increased TNFα during inflammation which activates astrocytic TNFR1.

    The hippocampus is the area of the brain involved in memory via a process called long-term potentiation which is produced by strengthening synaptic activity. This activity is subject to regulation by surrounding glial cells, and in the hippocampus gliotransmitters from astrocytes modulate synapses in cognitive circuits. The glial regulatory pathway itself is controlled by the cytokine tumour necrosis factor-alpha (TNFα). So it is not surprising there is interest in finding out what happens to the hippocampal cognitive circuit when TNFα increases above homeostatic levels (i.e. a state whereby internal conditions remain stable), as in inflammation. There already exists a link between TNFα levels and cognitive dysfunction in MS, but to date the mechanisms leading to this have remained elusive.

    The authors find that high levels of TNFα persistently alters the activity of this synaptic circuit via TNF receptor type 1 (TNFR1) in astrocytes leading to cognitive disturbances; primarily from increased glutamate mediated excitatory activity that reduces the dynamic range and impairs long-term potentiation. There also appears to be a time sensitive overlap with local inflammation restricted to the hippocampus than a generalised inflammatory state of the whole brain. It may even be distinct from the one causing motor symptoms, i.e. it is not a length dependent pathology.

    So it would appear that high levels of TNFα cause persistent synaptic alterations in the hippocampus that lead to cognitive dysfunction, and the astrocyte TNFR1 mediates this synaptic effect. Targeting astrocytic TNFR1 function, specifically blocking this may offer a promising treatment strategy for tackling the cognitive deficit in MS.

About the author

Neuro Doc Gnanapavan


    • Good question, some may debate that the different anti-TNF therapies work slightly differently. However, as far as this piece of work is concerned, the key would be to block at the receptor level and not neutralize TNF activity altogether. TNFa like everything else in the body has multiple roles, blocking higher up will therefore have multiple outcomes.

    • Then NDG I asked this because right here on the blog read a publication, made by the MD, on blocking TNFa worsening MS.
      And I think it was recently tested the Tolfacitinib, remedy for rheumatoid arthritis, in EAE mice and it seems that did not work out, the disease worsened very…



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