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

Neuron. 2020 Dec 9;108(5):887-904.e12. doi: 10.1016/j.neuron.2020.09.010. Epub 2020 Oct 6.


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.

Keywords: Down syndrome; Dp(16); Ts65Dn; acetaminophen; cognitive defects; dendritic spines; microglia; neurodevelopmental disorders; neuroinflammation; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Cognition / drug effects
  • Cognition / physiology*
  • Disease Models, Animal*
  • Down Syndrome / drug therapy
  • Down Syndrome / genetics*
  • Down Syndrome / physiopathology*
  • Female
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / physiology*
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use


  • Aminopyridines
  • Anti-Inflammatory Agents, Non-Steroidal
  • Pyrroles
  • pexidartinib