2. Academic Validation
  3. The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity

The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity

  • Immunity. 2018 May 15;48(5):979-991.e8. doi: 10.1016/j.immuni.2018.04.016.
Fabia Filipello 1,  Raffaella Morini 2,  Irene Corradini 3,  Valerio Zerbi 4,  Alice Canzi 1,  Bernadeta Michalski 5,  Marco Erreni 6,  Marija Markicevic 4,  Chiara Starvaggi-Cucuzza 2,  Karel Otero 7,  Laura Piccio 8,  Francesca Cignarella 8,  Fabio Perrucci 2,  Matteo Tamborini 2,  Marco Genua 6,  Lawrence Rajendran 9,  Elisabetta Menna 3,  Stefania Vetrano 1,  Margaret Fahnestock 5,  Rosa Chiara Paolicelli 9,  Michela Matteoli 10
Affiliations

Affiliations

  • 1 Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, 20090 Pieve Emanuele - Milan, Italy.
  • 2 Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano - Milan, Italy.
  • 3 Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano - Milan, Italy; IN-CNR, 20129 Milano, Italy.
  • 4 Neural Control of Movement Lab, HEST, ETH Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • 5 Department of Psychiatry & Behavioural Neurosciences, HSC-4N80, McMaster University, Hamilton, ON, Canada.
  • 6 Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano - Milan, Italy.
  • 7 Department of Neuroimmunology, Acute Neurology and Pain, Biogen Inc., 115 Broadway, Cambridge, MA, USA.
  • 8 Department of Neurology, Washington University, St. Louis, MO, USA.
  • 9 Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren, Switzerland.
  • 10 Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano - Milan, Italy; IN-CNR, 20129 Milano, Italy. Electronic address: michela.matteoli@hunimed.eu.
PMID: 29752066 DOI: 10.1016/j.immuni.2018.04.016
Abstract

The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an 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 for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2-/- mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated 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.

Keywords

PSD95; TREM2; autism; development; microglia; synapse; synaptic pruning.

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