Reduction of SynGAP-γ, disrupted splicing of Agap3 , and oligodendrocyte deficits in Srrm2 mice, a genetic model of schizophrenia and neurodevelopmental disorder

Rare loss-of-function (LoF) variants in SRRM2 , which encodes the SRRM2 splicing factor, are associated with schizophrenia and a neurodevelopmental disorder. How haploinsufficiency of SRRM2 leads to brain dysfunction is unknown. We find that Srrm2 ^+/- mice display (i) large-scale changes in gene expression in neuronal and glial cells, affecting synapse-related and other common molecular pathways across multiple brain regions, (ii) reduction of multiple key postsynaptic proteins, including the gamma isoform of SynGAP, itself encoded by a neurodevelopmental disorder risk gene, (iii) abnormal splicing and elevated expression of Agap3, a SynGAP interactor, (iv) reduced numbers of oligodendrocytes accompanied by decreased expression of myelin-related mRNAs and proteins, and (v) behavioral and EEG abnormalities, including reduction in sleep spindles that phenocopy humans with schizophrenia. Our findings provide insights into the molecular and neurobiological mechanisms of and potential therapeutic avenues for schizophrenia and the SRRM2 LoF neurodevelopmental disorder.