Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis

Erik Ellwardt, Gautam Pramanik, Dirk Luchtman, Tanja Novkovic, Eduardo Rosales Jubal, Johannes Vogt, Isabelle Arnoux, Christina Francisca Vogelaar, Shibajee Mandal, Melanie Schmalz, Zeke Barger, Inigo Ruiz de Azua, Tanja Kuhlmann, Beat Lutz, Thomas Mittmann, Stefan Bittner, Frauke Zipp*, Albrecht Stroh

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

49 Citations (Scopus)


Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+ imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.

Original languageEnglish
Pages (from-to)1392-1403
Number of pages12
JournalNature Neuroscience
Issue number10
Publication statusPublished - 1 Oct 2018
Externally publishedYes


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