Spatial and single-cell transcriptomics on SSPO PTV mutant mice reveals SCO-spondin’s function in mood regulation through brain barriers

The schizoaffective disorder presents mixed symptoms of schizophrenia and a mood disorder, posing an enormous challenge to its taxonomy and etiology. A recent hypothesis proposes independent genetic risk components from schizophrenia and affective disorders. By whole exome sequencing of a family with schizoaffective disorder, we identified four genes with protein-truncating variants (PTVs) that fit autosomal dominant inheritance model. Among these four genes, SSPO (encoding SCO-spondin) has exclusive expression in the subcommissural organ (SCO), a functionally highly intriguing organ in the brain, known to be potentially involved in CSF homeostasis. We generated a knock-in mouse model for the identified PTV of SSPO , and the mutant mice exhibited enhanced anxiety-like and anti-depression-like behaviors. We further performed multilayer transcriptomics analyses on the mouse brain, and found that the genes involved in stress response, anxiety, depression and bipolar disorder are dysregulated in the SCO and brain barriers, which have direct contact with CSF. Several cell-cell communication pathways involving brain barrier cells, including the WNT signaling pathways, are altered in the mutant mice. Our results demonstrate that SCO-spondin plays a key role in stress response and mood regulation through modulating brain barriers, and thus strongly suggest that the PTV of SSPO may contribute to the affective symptoms of schizoaffective disorder.