Chromosome 2q31.2 Deletion Impairs Neuronal Plasticity through Integrated Stress Response Activation

Rare genomic deletions disrupt gene networks essential for neural development and synaptic plasticity, yet their mechanistic effects remain poorly understood. Here, we investigated the impact of a chromosome 2q31.2 deletion using induced pluripotent stem cell (iPSC)-derived neural models from an affected individual and a genetically matched parental control. Differentiation into neural precursor cells and glial lineages was maintained, with subtle changes in cytoskeletal and lineage-associated gene expression. Transcriptomic analysis showed activation of oxidative stress, mitochondrial dysfunction, and degeneration-linked pathways, consistent with engagement of the integrated stress response (ISR). Pharmacologic inhibition of the ISR with ISRIB reduced ATF4 expression in neural precursors and mature neurons and increased CREB phosphorylation throughout development. Functionally, ISRIB improved neuronal network activity in cortical organoids, increasing calcium burst amplitude and synchronization after NMDA and AMPA stimulation. These results identify ISR dysregulation as a mechanistic link between chromosome 2q31.2 deletion and impaired neuronal plasticity, highlighting ISR modulation via ISRIB as a potential therapeutic approach.