TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Area of Science:

• Neuroscience
• Neuroimmunology
• Cell Biology

Background:

• Variants in the microglial receptor TREM2 (Triggering Receptor Expressed on Myeloid cells 2) are associated with increased risk for neurodegenerative diseases.
• The precise function of TREM2 in microglia and its role in modulating diverse neuropathologies remain largely unknown.
• Understanding TREM2's general function on microglia is critical for elucidating its contribution to brain health and disease.

Purpose of the Study:

• To investigate the general role of TREM2 on microglial function.
• To determine how the loss of TREM2 impacts microglial-mediated processes during neurodevelopment and in response to environmental stimuli.
• To identify novel mechanisms by which TREM2 influences synaptic integrity and neuroplasticity.

Main Methods:

• Analysis of microglial function in Trem2 knockout (Trem2-/-) mice.
• Assessment of synapse number and microglial-synaptic interactions in the cortex and hippocampus.
• Investigation of TREM2's role in astrocyte-mediated synaptic pruning.
• Evaluation of the effects of high-fat diet administration on synaptic integrity in Trem2-/- mice.

Main Results:

• Loss of TREM2 impairs neurodevelopment, leading to a significant reduction in synapse number in the cortex and hippocampus of young mice.
• TREM2 deficiency does not directly alter microglia-synapse interactions but is essential for microglia to limit excessive synaptic engulfment by astrocytes.
• While developmental synapse loss is largely normalized in adult Trem2-/- mice, high-fat diet reinitiates TREM2-dependent synapse loss.

Conclusions:

• Microglia, through TREM2, play a novel role in instructing astrocytes to regulate synaptic pruning and ensure proper synaptic refinement during development.
• TREM2 is a key regulator of synaptic homeostasis, influencing synapse number and stability.
• These findings suggest potential therapeutic strategies targeting TREM2 and microglial-astrocyte interactions for neurodegenerative diseases and brain injury.