Spatially resolved translational dysregulation in Grin2a +/- mouse model of schizophrenia

This is the authors' abstract. We don't add key points for this paper.

Loss-of-function (LoF) mutations of GRIN2A , encoding the GluN2A subunit of N-methyl-D-aspartate receptor (NMDAR), confer a high risk for schizophrenia (SCZ) 1–3 , yet how they affect diverse brain cell types remains poorly understood. Here, we combined subcellular-resolution spatial omics technologies, STARmap 4 and RIBOmap 5 , to jointly resolve single-cell transcriptomes and translatomes for 3,447 genes in the brains of Grin2a +/- mice and their wild-type littermates across 538,188 cells. Translational dysregulation was markedly more prominent than transcriptional changes in neurons. Across neuronal subtypes, a set of genes including Camk2a , Arc , Egr1 , Egr3 , Chmp2b , and Pja2 exhibited translational reduction in a Grin2a gene dose-dependent fashion, suggesting a connection between NMDAR hypofunction and reduced protein synthesis of downstream synaptic plasticity effectors. In interneurons (particularly parvalbumin interneurons), a strong reduction of Gad2 translation implies loss of inhibitory function in cortical microcircuits, which has long been hypothesized for SCZ pathophysiology. Non-neuronal cell types including astrocytes, oligodendrocytes, and vascular cells also exhibited region-specific translational changes in neurotransmitter transport, lipid synthesis, myelination, and stress response pathways, some of which co-varied with regional neuron state. Together, our study reveals brain-wide translation dysregulation as a critical mechanism underlying SCZ pathophysiology.