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bioRxiv · 10.64898/2025.12.23.696217

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

Wu, M.·Huang, J.·Aryal, S.·Farsi, Z.·Chen, H.·Zhou, Y.·Luo, S.·Wang, W. X.·Bonanno, K.·Yin, M.·Picard, I.·Dejanovic, B.·Keshishian, H.·Carr, S. A.·Sheng, M.·Wang, X.
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Abstract

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, STARmap4 and RIBOmap5, 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.

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Wu, M., Huang, J., Aryal, S., Farsi, Z., Chen, H., Zhou, Y., Luo, S., Wang, W. X., Bonanno, K., Yin, M., Picard, I., Dejanovic, B., Keshishian, H., Carr, S. A., Sheng, M., Wang, X.. 2025-12-24. Spatially resolved translational dysregulation in Grin2a+/- mouse model of schizophrenia. https://doi.org/10.64898/2025.12.23.696217

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