Editors' ChoiceNeuroscience

Impairing cognition with TNF-α

Sci. Signal.  05 Jan 2016:
Vol. 9, Issue 409, pp. ec1
DOI: 10.1126/scisignal.aaf1771

Infection and neurodegenerative diseases, including multiple sclerosis, are associated with cognitive defects and both are associated with increased inflammatory cytokines, such as tumor necrosis factor–α (TNF-α), in the brain. Because synaptic plasticity in the hippocampus is important for memory and cognition, Habbas et al. examined the effects of TNF-α on hippocampal glutamatergic synapses in mouse hippocampal slice preparations. Application of 600 pM of TNF-α, but not of a low concentration (60 pM), increased presynaptic activity as measured by the frequency of miniature postsynaptic excitatory currents (mEPSCs). This increase in mEPSC frequency induced by 600 pM TNF-α was absent upon preincubation of wild-type hippocampal slices with an antagonist of the NMDA-type glutamate receptor or in hippocampal slices from mice globally deficient in the TNF receptor (tnfr1–/–). Selective reintroduction of TNFR1 into astrocytes in tnfr1–/– mice rescued the synaptic plasticity–inducing effects of TNF-α on the hippocampal slices, indicating that TNF-α acted at astrocytes, which then signaled to the neurons to increase presynaptic activity. AT-EAE mice are a model of multiple sclerosis, and compared with control mice, AT-EAE mice exhibited impaired fear learning and memory, which correlated with increased TNF-α and an accumulation of microglia and leukocytes in the relevant region of the hippocampus. Hippocampal slices from AT-EAE mice showed an increase in mEPSC frequency that was blocked by treating the mice with the NDMA receptor antagonist. Analysis of fear memory in the AT-EAE model comparing control tnfr1–/– and mice in which TNFR was selectively restored in astrocytes confirmed that the astrocyte response to TNF-α contributed to impaired fear conditioning and memory. Because inflammatory responses are necessary for neuronal injury repair, yet also contribute to long-term neuronal dysfunction, this study suggests that it may be possible to selectively target pathological effects, such as impaired cognition, in neurodegenerative diseases without blocking the beneficial effects of inflammatory responses (see Osso and Chan).

S. Habbas, M. Santello, D. Becker, H. Stubbe, G. Zappia, N. Liaudet, F. R. Klaus, G. Kollias, A. Fontana, C. R. Pryce, T. Suter, A. Volterra, Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell 163, 1730–1741 (2015). [PubMed]

L. A. Osso, J. R. Chan, Astrocytes underlie neuroinflammatory memory impairment. Cell 163, 1574–1576 (2015). [PubMed]