Lack of the microglial innate immune receptor TREM2 results in defective synapse elimination and altered brain connectivity Fabia Filipello1#, Raffaella Morini2#, Irene Corradini2,3, Valerio Zerbi4, Alice Canzi1, Bernadeta Michalski5, Marco Erreni6, Marija Markicevic4, Chiara Starvaggi-Cucuzza 2, Karel Otero7, Laura Piccio 8, Francesca Cignarella 8, Fabio Perrucci 2, Matteo Tamborini 2, Marco Genua1, Lawrence Rajendran9, Elisabetta Menna2,3, Stefania Vetrano1, Margaret Fahnestock5, Rosa Chiara Paolicelli9, Michela Matteoli1,3 1Humanitas University, Department of Biomedical Sciences, Pieve Emanuele - Milan, Italy; 2Laboratory of Pharmacology and Brain Pathology, Neurocenter IRCCS Humanitas, Rozzano - Milan, Italy; 3IN-CNR, 20129 Milano, Italy; 4Neural Control of Movement Lab, HEST, ETH Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; 5Department of Psychiatry & Behavioural Neurosciences, HSC-4N80 McMaster University, Hamilton, Ontario, Canada 6Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano- Milan, Italy; 7Department of Neuroimmunology, Acute Neurology and Pain, Biogen Inc, 115 Broadway, Cambridge, USA; 8Department of Neurology, Washington University, St. Louis, MO, USA; 9San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; 9Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren, Switzerland #These authors contributed equally
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor, associated with a lethal form of early, progressive dementia, the Nasu-Hakola disease, and with increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of TREM2 inactivating mutations. Here we show that TREM2 is essential to microglia in order to perform synaptic refinement during early stages of brain development. The absence of TREM2 results in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2-/- mice display repetitive behavior and altered sociability. Also, TREM2 protein levels negatively correlate with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases.
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