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Published on: June 30, 2023
The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity
Fabia Filipello1, Raffaella Morini2, Irene Corradini3
1Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, 20090 Pieve Emanuele - Milan, Italy.
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.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) is vital for brain development, influencing synapse elimination and neuronal connectivity. This microglial receptor
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor linked to neurodegenerative diseases like Alzheimer's.
- TREM2 dysfunction is hypothesized to cause microglial phagocytosis defects, contributing to pathology.
Purpose of the Study:
- To investigate the role of TREM2 in early brain development and neuronal circuit formation.
- To explore the potential involvement of TREM2 in neurodevelopmental disorders.
Main Methods:
- Utilized Trem2 knockout (Trem2-/-) mouse models.
- Assessed synaptic refinement, neurotransmission, and functional connectivity.
- Observed behavioral phenotypes including repetitive behavior and sociability.
- Correlated TREM2 protein levels with autism symptom severity in human subjects.
Main Results:
- TREM2 is essential for microglia-mediated synapse elimination during brain development.
- Absence of Trem2 leads to impaired synapse pruning, increased excitatory neurotransmission, and reduced functional connectivity.
- Trem2-/- mice exhibit abnormal repetitive behaviors and altered social interactions.
- Human studies show a negative correlation between TREM2 levels and autism symptom severity.
Conclusions:
- TREM2 plays a critical role in sculpting neuronal circuits during early brain development.
- These findings implicate TREM2 in the pathophysiology of neurodevelopmental diseases, including autism.
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