Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome

Microglia are brain-resident immune cells and regulate mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by a supernumerary chromosome 21, containing also genes related to the immune system. In the hippocampus of the Dp(16) mouse model of DS and DS individuals, we found activated microglia, as assessed by their morphology; activation markers; and, for DS mice, electrophysiological profile. Accordingly, we found increased pro-inflammatory cytokine levels and altered interferon signaling in Dp(16) hippocampi. DS mice also showed decreased spine density and activity of hippocampal neurons and hippocampus-dependent cognitive behavioral deficits. Depletion of defective microglia or treatment with a commonly used anti-inflammatory drug rescued the neuronal spine and activity impairments and cognitive deficits in juvenile Dp(16) mice. Our results suggest an involvement of microglia in Dp(16)-mouse cognitive deficits and identify a new potential therapeutic approach for cognitive disabilities in DS individuals. [Display omitted] •DS mice display microglia alterations and cognitive impairment•Depletion of microglia rescues cognitive impairment in DS mice•Acetaminophen treatment rescues microglia and cognitive impairments in DS mice•Brain samples of DS people recapitulate microglia alterations observed in DS mice Pinto, Morelli et al. identify a critical role for activated microglia in cognitive impairments of Down syndrome mouse models that can be ameliorated by either depleting microglia or using anti-inflammatory drugs to reduce microglia activation. In this work, microglia activation is also revealed in brains of people with Down syndrome.