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Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling
Open accessAbstract
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.
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“Reactive microglia may shift astrocyte signaling from physiological to pathological by increasing production of tumor necrosis factor α (TNFα), thus altering synaptic functions and behavior57.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [57]
In the citing paper
“In particular, in EAE mice, a local inflammatory focus in dorsal hippocampus caused TNFα increase s, longlasting modification of excitatory neurotransmission and impaired contextual memory.”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [62]
In the citing paper
“These effects depend on enhanced TNFα signal ing via its astrocytic type-1 receptor (TNFR1), which hijacked the regulatory mechanism controlling astrocytic glutamate release (see above) and caused long-lasting potentiation of excitatory synapses.”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [62]
In the citing paper
“This synaptic and behavioral phenotype was abolished in global TNFR1 knockout EAE mice and could be restored by inducing re-expression of the receptor solely in astrocytes (Table 1), demonstrating that astrocytes mediate the deleterious action of TNFα on memory function in EAE mice 62 .”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [62]
In the citing paper
“An example of this was observed in the experimental autoimmune encephalitis (EAE) model of multiple sclerosis, where abnormal TNFα -dependent signaling by astrocytes causes cognitive deficits resembling those seen in patients 62 (Fig. 4d).”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [62]
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Metadata
- Authors
- Habbas, S., Santello, M., Becker, D., Stubbe, H., Zappia, G., Liaudet, N., Klaus, F. R., Kollias, G., Fontana, A., Pryce, C. R., Suter, T., & Volterra, A.
- Affiliations
- University of Lausanne (CH)
- University of Zurich (CH)
- Alexander Fleming Biomedical Sciences Research Center (GR)
- University Hospital Zurich (CH)
- Corresponding author
- Volterra, Andrea
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 163
- Issue
- 7
- Pages
- 1730-1741
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2190725993
- Cited by
- 347
- References
- 52
- Citations by year
- 2026: 25 · 2025: 28 · 2024: 28 · 2023: 31 · 2022: 43 · 2021: 42 · 2020: 35 · 2019: 41 · 2018: 30 · 2017: 29 · 2016: 14 · 2015: 1
- FWCI
- 13.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- IRIS (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (140999, 141137, 31003A)
- Université de Lausanne
- Universität Zürich
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- TNF-α, TNFR1, astrocytes, astrocyte-neuron communication, hippocampus, dentate gyrus, synaptic plasticity, memory impairment, contextual learning, experimental autoimmune encephalitis, multiple sclerosis, neuroinflammation, cognitive impairment
- MeSH terms
- Animals, Astrocytes, Encephalomyelitis, Autoimmune, Experimental, Humans, Learning, Memory, Multiple Sclerosis, Piperidines, Tumor Necrosis Factor-alpha, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Dentate Gyrus, Receptors, Tumor Necrosis Factor, Type I, Mice
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