Astrocytes regulate spatial memory in a sex-specific manner

Cognitive processes and neurocognitive disorders are regulated by astrocytes and have prominent sex differences. However, the contribution of astrocytes to sex differences is not known. We leveraged astrocyte-targeted gene editing and chemogenetics in adult mice to reveal that astrocytic glutamate receptors and other G protein-coupled receptors (GPCRs) modulate hippocampus-dependent cognitive function in a sexually dimorphic manner. In females, spatial memory was improved by increasing metabotropic glutamate receptor 3 (mGluR3) in astrocytes or stimulating astrocytic G i/o -coupled signaling, whereas stimulating G s -coupled signaling impaired memory. However, in males, memory was improved by reducing mGluR3 or stimulating G s -coupled signaling, whereas stimulating G i/o -coupled signaling impaired memory. Thus, memory requires a sex-specific balance of astrocytic G s -coupled and G i/o -coupled receptor activities, and disease-associated alterations or therapeutic targeting of these pathways may cause opposing sex-dependent effects on cognitive function. Summary Glia cause sex-specific changes in cognition