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Cognitive impairment (CI) is a disabling concomitant of multiple sclerosis (MS) with a complex and controversial pathogenesis. The cytokine interleukin-17A (IL-17A) is involved in the immune pathogenesis of MS, but its possible effects on synaptic function and cognition are still largely unexplored. In this study, we show that the IL-17A receptor (IL-17RA) is highly expressed by hippocampal neurons in the CA1 area and that exposure to IL-17A dose-dependently disrupts hippocampal long-term potentiation (LTP) through the activation of its receptor and p38 mitogen-activated protein kinase (MAPK). During experimental autoimmune encephalomyelitis (EAE), IL-17A overexpression is paralleled by hippocampal LTP dysfunction. An in vivo behavioral analysis shows that visuo-spatial learning abilities are preserved when EAE is induced in mice lacking IL-17A. Overall, this study suggests a key role for the IL-17 axis in the neuro-immune cross-talk occurring in the hippocampal CA1 area and its potential involvement in synaptic dysfunction and MS-related CI. [Display omitted] • Hippocampal neurons express IL-17RA both under control conditions and during EAE • IL-17A dose-dependently blocks LTP via the activation of IL-17RA and p38 MAPK • Hippocampal IL-17A overexpression and synaptic dysfunction both occur during EAE • The lack of IL-17A ameliorates EAE-related cognitive deficits In this study, Di Filippo et al. investigate the pathogenesis of hippocampal synaptopathy in experimental autoimmune encephalomyelitis, highlighting an IL-17A-centered neuro-immune cross-talk. Besides its well-known immunopathogenic roles, the IL-17 axis might be directly involved in the modulation of synaptic plasticity and cognition, with potential therapeutic implications for people with multiple sclerosis. [ABSTRACT FROM AUTHOR]