Perturbed cell fate decision by schizophrenia-associated AS3MT^d2d3 isoform during corticogenesis

The neurodevelopmental theory of schizophrenia emphasizes early brain development in its etiology. Genome-wide association studies have linked schizophrenia to genetic variations of AS3MT (arsenite methyltransferase) gene, particularly the increased expression of AS3MT^d2d3 isoform. To investigate the biological basis of this association with schizophrenia pathophysiology, we established a transgenic mouse model (AS3MT^d2d3-Tg) ectopically expressing AS3MT^d2d3 at the cortical neural stem cells. AS3MT^d2d3-Tg mice exhibited enlarged ventricles and deficits in sensorimotor gating and sociability. Single-cell and single-nucleus RNA sequencing analyses of AS3MT^d2d3-Tg brains revealed cell fate imbalances and altered excitatory neuron composition. AS3MT^d2d3 localized to centrosome, disrupting mitotic spindle orientation and differentiation in developing neocortex and organoids, in part through NPM1 (Nucleophosmin 1). The structural analysis identified that hydrophobic residues exposed in AS3MT^d2d3 are critical for its pathogenic function. Therefore, our findings may help to explain the early pathological features of schizophrenia.