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. | PubMed

Bruno Pinto¹, Giovanni Morelli², Mohit Rastogi², Annalisa Savardi², Amos Fumagalli², Andrea Petretto³, Martina Bartolucci³, Emilio Varea⁴, Tiziano Catelani⁵, Andrea Contestabile², Laura E Perlini², Laura Cancedda⁶

1. BIO@SNS, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
2. Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
3. Core Facilities - Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
4. Cellular Biology Department, University of Valencia, Valencia, Spain.
5. Electron Microscopy Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
6. Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy; Dulbecco Telethon Institute, Rome, Italy. Electronic address: laura.cancedda@iit.it.

Abstract

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.

Presented By Giovanni Morelli | ORCID iD