GSE137939
Rescuing over-activated microglia by acetaminophen treatment restores cognitive performance in the Dp(16) mouse model of Down syndrome.
Microglia are the resident immune cells of the brain and have been implicated in mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by the presence of a supernumerary chromosome 21, which contains genes essential for the function of the immune system. Here, we investigated the presence of microglial alterations and their implication for cognitive impairment in the Dp(16) mouse model of DS. In the hippocampus of Dp(16) mice and individuals with DS, we found microglial morphology indicative of an activated state. Accordingly, we found an electrophysiological profile typical of activated microglia, increased levels of pro-inflammatory cytokines, and altered interferon signaling in Dp(16) mice. In addition, DS mice showed decreased neuronal spine density and neuronal activity, as well as cognitive behavioral deficits. Remarkably, depletion of defective microglia by PLX3397 treatment or rescue of the microglia activated state by the commonly used anti-inflammatory drug acetaminophen rescued the neuronal deficits and cognitive impairment in Dp(16) mice. Our data suggest an involvement of microglia in the cognitive impairment of DS animals and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS. Overall design: 4 Down syndrome and 5 neurologically normal control samples from post-mortem human subjects