The subcommissural organ secretes SCO-spondin, associated with stress response and mood

The subcommissural organ (SCO) is an evolutionarily conserved structure in the brains of vertebrates, but its function remains largely unknown. The protein SCO-spondin, exclusively produced by the SCO, may hold the key to understanding its function. Here, by whole exome sequencing of a family with schizoaffective disorder, we identified a protein-truncating variant (PTV) mutation in the SCO-spondin gene ( SSPOP ) segregating with this disease. To explore the potential role of this gene in this mood disorder, we generated a mouse model carrying this mutation in the SCO-spondin gene ( Sspo ). We conducted behavioral tests and multi-omics studies on male mice. The mouse model exhibited abnormal mood-related behaviors, including heightened anxiety, reduced stress-induced depression-like behaviors, and increased prepulse inhibition. Multi-transcriptomics, encompassing whole-brain, spatial, and single-cell transcriptomics, revealed dysregulated genes in the SCO and CSF-contacting brain regions. These genes are linked to stress response and human mood disorders, involving molecular pathways and cell-cell communications related to the CSF-barrier cells. This comprehensive study elucidates the role of SCO in stress response and mood regulation through a novel regulatory axis: the SCO-CSF-barrier axis.