Microglia mediated by LAG3 regulate astrocyte morphogenesis in the brain white matter

Microglia display dynamic morphological and functional heterogeneity during brain development, yet the molecular mechanisms governing their regional specialization remain unclear. We report that lymphocyte-activation gene 3 (Lag3) is highly expressed in white matter amoeboid microglia at postnatal day 7. Conditional deletion of Lag3 in microglia (Lag3^cKO-Cx3) specifically reduces microglial density and activation in the white matter, without affecting gray matter microglia. This microglial alteration further reduces the morphological complexity of the surrounding astrocytes in Lag3^cKO-Cx3 mice but has no significant effects on oligodendrocytes or neuronal axons. Behavioral tests show no deficits despite these glial abnormalities. Mechanistically, reduced p38MAPK phosphorylation in the white matter microglia of Lag3^cKO-Cx3 mice decreases the expression of GITRL, a downstream ligand interacting with astrocytes, leading to dysregulation of mTOR signaling in astrocytes. Thus, Lag3-mediated regulation of postnatal white matter amoeboid microglial abundance and activation influences astrocyte morphology while revealing microglial heterogeneity and microglia-astrocyte communication.