A thioredoxin-Serinc2-lipid signaling axis modulates mood-related behaviors in mice

Bipolar disorder (BD) shows strong heritability and distinct symptomatic subtypes. However, the molecular basis underlying subtype-specific features remains poorly understood. Here, we identified Serinc2, a BD susceptibility gene encoding a L-serine transporter that regulates membrane lipid synthesis, as a regulator of mood-related behavioral phenotypes. Using patient plasma samples, BD iPSC-derived forebrain organoids, and Serinc2 knockout/overexpression mouse models, we found that Serinc2 expression was increased in bipolar I (BDI) but decreased in bipolar II (BDII); bi-directional manipulation of Serinc2 induced opposite changes in synaptic transmission and depression-related behaviors, accomplied by alterations in PS/SM-dependent redistribution of NMDAR subunits in postsynaptic membranes. Mechanistically, we found that thioredoxin (Txn) bound to the Serinc2 regulatory region and negatively regulate its transcription, and that differential chromatin accessibility of Txn contributed to subtype-associated expression patterns. Together, our results demonstrated a Txn-Serinc2-lipid signaling axis that linked membrane lipid composition to synaptic function and mood-related behaviors, and indicated a potential molecular framework contributing to subtype-specific features of BD.