Microglia contribute to bipolar depression through Serinc2-dependent phospholipid synthesis

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Microglia play a role in bipolar disorder (BD) pathogenesis through inflammatory and immune responses.
• The specific contribution of microglia to BD remains incompletely understood.

Purpose of the Study:

• To investigate the role of Serine-3 (Serinc2) in BD susceptibility and pathogenesis.
• To elucidate the mechanisms by which microglial Serinc2 influences BD-related behaviors.

Main Methods:

• Analysis of Serinc2 expression in BDII patient plasma.
• Utilized induced pluripotent stem cell (iPSC)-derived microglia-like cells from BDII patients.
• Generated microglia-specific Serinc2-deficient mouse models.
• Combined iPSC-microglia and mouse models to study Serinc2 function.

Main Results:

• Reduced Serinc2 expression was observed in BDII patient plasma and iPSC-derived microglia, correlating with disease severity.
• Microglial Serinc2 deficiency led to decreased synaptic pruning and depression-like behaviors in mice.
• Serinc2 deficits impaired serine-related phospholipid synthesis, affecting microglial membrane CR3 formation and synaptic pruning signals.

Conclusions:

• Microglial Serinc2 deficits are associated with BD susceptibility and pathogenesis.
• Impaired synaptic pruning due to Serinc2-dependent lipid alterations contributes to BD-related behavioral abnormalities.
• Serinc2 represents a potential target for understanding and treating BD.