Astrocytic MEGF10 Upregulation for Selective Synaptic Engulfment Control

Astrocytes express multiple phagocytic receptors including MEGF10 (multiple EGF-like domains 10) that enable direct synaptic material engulfment independent of microglial activation. This hypothesis proposes that targeted upregulation of astrocytic MEGF10 expression can provide more precise temporal and spatial control over synaptic pruning compared to microglial TREM2 activation. MEGF10 functions through recognition of phosphatidylserine exposure on synaptic terminals marked for elimination, triggering astrocytic process extension and direct engulfment of synaptic material. Unlike the inflammatory cascades associated with microglial activation, astrocytic MEGF10-mediated pruning operates through gentler phagocytic mechanisms that preserve local tissue architecture. The hypothesis predicts that astrocyte-specific MEGF10 overexpression using GFAP-driven vectors will enhance developmental synaptic refinement in neural circuits while avoiding the potential neuroinflammatory side effects of microglial stimulation. This approach could be particularly valuable for correcting aberrant connectivity patterns in neurodevelopmental disorders where excessive or insufficient synaptic pruning contributes to circuit dysfunction. Experimental validation would involve comparing synaptic density changes, electrophysiological connectivity measures, and inflammatory marker expression between MEGF10-upregulated and TREM2-activated conditions in both developmental and adult brain tissue models.