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

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Microglia exhibit regional heterogeneity in morphology and function during brain development.
• Molecular mechanisms driving microglial specialization remain largely unknown.
• Lymphocyte-activation gene 3 (Lag3) expression in developing brain microglia is unexplored.

Purpose of the Study:

• To investigate the role of Lag3 in regulating regional microglial specialization during postnatal brain development.
• To elucidate the molecular mechanisms by which Lag3 influences white matter microglia and their interactions with other glial cells.

Main Methods:

• Conditional knockout mouse model (Lag3^cKO-Cx3) to delete Lag3 specifically in microglia.
• Immunohistochemistry and morphological analysis to assess microglial density, activation, and astrocyte complexity.
• Western blotting to analyze signaling pathways (p38MAPK, mTOR).
• Behavioral testing to evaluate functional deficits.

Main Results:

• Lag3 is highly expressed in postnatal day 7 white matter amoeboid microglia.
• Conditional deletion of Lag3 in microglia (Lag3^cKO-Cx3) specifically reduced white matter microglial density and activation.
• Lag3 deficiency in microglia altered astrocyte morphology but did not affect oligodendrocytes or neuronal axons.
• Mechanistically, Lag3 deletion reduced p38MAPK phosphorylation, decreased GITRL expression, and dysregulated astrocyte mTOR signaling.

Conclusions:

• Lag3 plays a critical role in regulating the abundance and activation of postnatal white matter microglia.
• Lag3-mediated microglial regulation influences astrocyte morphology through microglia-astrocyte communication pathways.
• This study reveals Lag3 as a key factor in microglial regional specialization and highlights its impact on glial interactions during brain development.