Astrocytic RNA degradation suppresses 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 Ca2+ signaling coupled with synapse dysfunction and elevated anxiety. Restoring basal Ca2+ 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 functional roles for NMD in astrocytes. SIGNIFICANCE STATEMENTNon-sense mediated mRNA Decay (NMD) is the only RNA regulatory pathway linked to numerous neurodevelopmental and neuropsychiatric conditions, such as autism spectrum disorders and schizophrenia. To date, several studies indicate the NMD pathway regulates specific mRNAs to support fundamental neuronal processes in the mammalian brain. Yet, the biological role of NMD in brain astrocytes remains unknown. This study identifies the mRNA transcripts targeted by NMD and characterizes their contribution to critical neuro-glia interactions supporting proper brain function. In doing so, our work advances our knowledge of glial RNA biology in health and disease.