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

Raffaella Morini, Fabia Filipello, Irene Corradini, Valerio Zerbi, Alice Canzi, Bernadeta Michalski, Marco Erreni, Marija Markicevic, Chiara Starvaggi-Cucuzza, Karel Otero, Laura Piccio, Francesca Cignarella, Fabio Perrucci, Matteo Tamborini, Marco Genua, Lawrence Rajendran, Elisabetta Menna, Stefania Vetrano, Margaret Fahnestock, Rosa Chiara PaolicelliMichela Matteoli

Research output: Contribution to journalArticle

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. TREM2 is a microglial innate immune receptor whose functions during brain development are still unknown. Filipello et al. demonstrate that TREM2 is essential for microglia to eliminate supernumerary synapses in the developing brain. TREM2 protein was also reduced in autistic patients, suggesting that the receptor may be involved in neurodevelopmental diseases.

Original languageEnglish
Pages (from-to)979-991.e8
JournalImmunity
Volume48
Issue number5
DOIs
Publication statusPublished - May 15 2018

Keywords

  • autism
  • development
  • microglia
  • PSD95
  • synapse
  • synaptic pruning
  • TREM2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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  • Cite this

    Morini, R., Filipello, F., Corradini, I., Zerbi, V., Canzi, A., Michalski, B., Erreni, M., Markicevic, M., Starvaggi-Cucuzza, C., Otero, K., Piccio, L., Cignarella, F., Perrucci, F., Tamborini, M., Genua, M., Rajendran, L., Menna, E., Vetrano, S., Fahnestock, M., ... Matteoli, M. (2018). The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity. Immunity, 48(5), 979-991.e8. https://doi.org/10.1016/j.immuni.2018.04.016