SRRM2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a mouse model of schizophrenia

Abstract

Rare loss-of-function variants in SRRM2, which encodes a nuclear speckle scaffold and splicing factor, are associated with schizophrenia and neurodevelopmental disorders. How SRRM2 haploinsufficiency disrupts brain function is unknown. We find that Srrm2+/- mice exhibit (i) large-scale changes in gene expression in neuronal and glial cells, affecting DNA-binding-, synapse-, translation-, mitochondria-related pathways across multiple brain regions; (ii) alterations in splicing and/or abundance of multiple postsynaptic proteins, including reduction of the gamma isoform of SynGAP and elevation of its interactor, Agap3; and (iii) reduced oligodendrocyte proportions, particularly in striatum, accompanied by decreased expression of myelin-related mRNAs and proteins. Human iPSC-derived neurons deficient in SRRM2 display conserved AGAP3 splicing defects. Behaviorally, Srrm2+/- mice have reduced locomotor activity and impaired startle responses, and EEG recordings reveal reduced sleep spindles resembling humans with schizophrenia. Our findings identify specific synaptic changes, splicing dysregulation, and impaired myelination as mechanisms linking SRRM2 haploinsufficiency to neuropsychiatric disease.