TREM2-Mediated Microglial Regulation of Oligodendrocyte Precursor Cell Recruitment for Circuit-Specific Remyelination

This hypothesis proposes that activated microglia use TREM2 signaling to coordinate both synaptic pruning and oligodendrocyte precursor cell (OPC) recruitment in a spatially and temporally coupled manner. When microglia identify synapses for pruning through TREM2-dependent recognition of ‘eat-me’ signals, they simultaneously release specific chemokines (CCL2, CXCL12) and growth factors (PDGF-AA, FGF2) that recruit OPCs to the same neural circuits. This creates a coordinated remodeling process where synaptic elimination is followed by targeted remyelination of the remaining, strengthened connections. The TREM2 activation state determines both the specificity of synaptic pruning and the magnitude of OPC recruitment signals, ensuring that structural connectivity restoration occurs precisely where functional connectivity has been refined. In neurodegenerative diseases, this coordinated process becomes dysregulated—either through TREM2 dysfunction leading to inappropriate pruning, or through impaired microglial-OPC communication resulting in failed remyelination. The hypothesis predicts that enhancing TREM2 function will restore both appropriate synaptic selection and subsequent myelin repair in the same neural circuits. This can be tested by measuring synaptic density, myelin thickness, and OPC differentiation in TREM2-deficient versus TREM2-enhanced conditions, with the prediction that optimal outcomes require coordinated rather than independent activation of these processes. Therapeutic interventions targeting this axis could simultaneously address synaptic loss and white matter degradation through a unified microglial-mediated mechanism.