Mapping the ISR Landscape in Cognitive Disorders via single-cell multi-omics

Persistent activation of the integrated stress response (ISR) is a central driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. However, the cell-type-specific mechanisms underlying these deficits remain poorly understood. Here, by integrating single-cell RNA-seq and single-cell ATAC-seq, we generated an ISR atlas of the brain using Ppp1r15bR658C mice, a clinically relevant model of intellectual disability characterized by selective and persistent ISR activation. Unexpectedly, our analysis revealed that distinct brain cell types differentially engage transcriptional and chromatin remodeling programs. Notably, selective deletion of the major ISR downstream effector ATF4 in GABAergic neurons—but not in glutamatergic neurons—impacts ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes have different dependencies for ISR effectors. Finally, we defined a molecular single-cell signature of persistent ISR activation that serves as a metric of ISR-mediated cellular vulnerability, and as a biomarker for cognitive dysfunction across human cogntive disorders. These findings dissect the cell-type-specific architecture of the ISR in the brain, providing new insights into the biological mechanisms driving ISR-dependent cognitive decline.