Astrocytic Gi-GPCR activation enhances stimulus-evoked extracellular glutamate

Astrocytes perform critical functions in the nervous system, many of which are dependent on neurotransmitter-sensing through G protein-coupled receptors (GPCRs). However, whether specific astrocytic outputs follow specific GPCR activity remains unclear, and exploring this question is critical for understanding how astrocytes ultimately influence brain function and behavior. Here, we investigate the outputs of astrocytic Gi-GPCRs, a family of GPCRs which we previously showed is sufficient to increase slow-wave neural activity (SWA) during sleep when activated in cortical astrocytes1. We focus on two putative outputs by astrocytes in vivo, the regulation of extracellular glutamate and GABA, by combining fiber photometry recordings of the extracellular indicators iGluSnFR and iGABASnFR with astrocyte-specific chemogenetic Gi-GPCR activation. We find that Gi-GPCR activation does not change spontaneous dynamics of extracellular glutamate or GABA. However, Gi-GPCR activation does specifically increase visual stimulus-evoked extracellular glutamate. Together, these data point towards a complex relationship between astrocytic inputs and outputs in vivo that may depend on behavioral context. Further, they suggest an extracellular glutamate-specific mechanism underlying some astrocytic Gi-GPCR-dependent behaviors, including the regulation of sleep SWA.