Journal Article

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

Carr, Steven A, Wu, Mingrui, Farsi, Zohreh, Aryal, Sameer, Keshishian, Hasmik, Sheng, Morgan, Chen, Hongyu, Bonanno, Kevin, Yin, Margaret, Luo, Shuchen, Huang, Jiahao, Dejanovic, Borislav, Picard, Inès, Zhou, Yiming, Wang, Wendy Xueyi, Wang, Xiao

2025

Overview

Loss-of-function (LoF) mutations of , encoding the GluN2A subunit of N-methyl-D-aspartate receptor (NMDAR), confer a high risk for schizophrenia (SCZ) , yet how they affect diverse brain cell types remains poorly understood. Here, we combined subcellular-resolution spatial omics technologies, STARmap and RIBOmap , to jointly resolve single-cell transcriptomes and translatomes for 3,447 genes in the brains of +/- 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 , , , , , and exhibited translational reduction in a 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 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.