Astrocytic Nonsense-mediated mRNA decay regulates calcium signaling to support synapse function and restrain anxiety

How astrocytes achieve their diverse roles in the brain at the molecular level is poorly understood. In this study, we leverage mouse models, electrophysiology, calcium imaging, behavioral assays, and bioinformatic approaches to demonstrate that astrocyte activity and astrocyte-mediated mouse behavior depends on the highly conserved and selective RNA turnover pathway-nonsense-mediated RNA decay (NMD). Conditional deletion of the core NMD gene, Upf2 , in mature astrocytes leads to enhanced basal Ca ²⁺ signaling coupled with synapse dysfunction and elevated anxiety. Restoring basal Ca ²⁺ signaling in NMD-deficient astrocytes rescued synaptic transmission and minimized anxiety-associated behavior. Molecular bioinformatic analysis identified specific NMD target transcripts in astrocytes as candidates influencing calcium signaling pathways and neuro-glia interactions that support brain function. Our study is the first to demonstrate specific roles for NMD in astrocytes.