New study links gene, lipid signaling to bipolar disorder

A newly identified molecular axis may explain key differences between the two main subtypes of bipolar disorder. Research published in Nature has linked the gene Serinc2, a known genetic risk factor for the condition, to specific changes in brain cell membranes and synaptic function that correlate with distinct mood-related behaviors.

Scientists found that expression of the Serinc2 gene was increased in individuals with bipolar I disorder (BDI) but decreased in those with bipolar II disorder (BDII). The gene encodes a protein that transports the amino acid L-serine, a key building block for synthesizing specific membrane lipids. The study's authors, using a combination of human plasma samples, stem cell-derived brain organoids from patients, and genetically engineered mouse models, propose that this bidirectional change in Serinc2 activity drives opposing effects on synaptic transmission and depression-like behaviors.

The Serinc2-lipid connection

Manipulating Serinc2 levels in mice produced opposite behavioral outcomes. Increasing Serinc2 expression led to depression-related behaviors, while knocking it out produced an anti-depressant effect. The researchers traced this effect to changes in the lipid composition of postsynaptic membranes, specifically the balance of phosphatidylserine (PS) and sphingomyelin (SM). These lipid alterations, in turn, affected the distribution and function of NMDA receptor subunits, which are critical for synaptic communication and plasticity.

This work positions Serinc2 as a central regulator connecting genetic susceptibility to the cellular mechanics of mood regulation. "Our results demonstrated a Txn-Serinc2-lipid signaling axis that linked membrane lipid composition to synaptic function and mood-related behaviors," the authors wrote, indicating a potential molecular framework for the subtype-specific features of bipolar disorder.

A regulatory role for thioredoxin

The study also uncovered the mechanism controlling Serinc2's subtype-specific expression patterns. The protein thioredoxin (Txn) was found to bind to the regulatory region of the Serinc2 gene and repress its transcription. The researchers discovered that differences in chromatin accessibility-how open the DNA is for transcription factors to bind-for the Txn gene were associated with the divergent Serinc2 levels seen in BDI versus BDII. This suggests that epigenetic regulation of Txn contributes to the distinct molecular profiles of the two bipolar disorder subtypes.

Research methods and data

The investigation employed a multi-pronged approach to validate its findings across different systems. The team analyzed plasma from patients with bipolar disorder, created forebrain organoids from induced pluripotent stem cells (iPSCs) derived from patients, and conducted behavioral and molecular tests on Serinc2 knockout and overexpression mouse models. Key datasets from the study, including RNA sequencing, assay for transposase-accessible chromatin sequencing (ATAC-seq), and lipidomics data, have been made publicly available in major biological repositories.

Implications for understanding bipolar disorder

The findings offer a more detailed picture of how a genetic risk factor might translate into the clinical reality of bipolar disorder. By tying Serinc2 activity to specific changes in synaptic lipids and receptor function, the research moves beyond genetic association to propose a testable biological pathway. The opposing expression patterns in BDI and BDII provide a rare molecular correlate for the symptomatic differences between these subtypes, which include the presence of full manic episodes in BDI and only hypomanic episodes in BDII. The study concludes by highlighting the Txn-Serinc2-lipid signaling axis as a contributor to the subtype-specific features of the illness.