Specific and behaviourally consequential astrocyte Gq GPCR signaling attenuation in vivo with iβARK

Astrocytes respond to neurotransmitters and neuromodulators using G protein-coupled receptors (GPCRs) to mediate physiological responses. Despite their importance, there has been no method to genetically, specifically, and effectively attenuate astrocyte G q GPCR pathways to explore consequences of this prevalent signaling mechanism in vivo . We report a 122 residue inhibitory peptide from β adrenergic receptor kinase 1 (iβARK and inactive D110A control) to attenuate astrocyte G q GPCR signaling. iβARK significantly attenuated G q GPCR Ca 2+ signaling in brain slices and in vivo , altered behavioral responses, spared other GPCR responses, and did not alter astrocyte spontaneous Ca 2+ signals, morphology, electrophysiological properties or gene expression in the striatum. Furthermore, brain wide attenuation of astrocyte G q GPCR signaling with iβARK using PHP.eB AAVs, when combined with c-Fos mapping, suggested nucleispecific contributions to behavioral adaptation and spatial memory. iβARK extends the toolkit needed to explore functions of astrocyte G q GPCR signaling within neural circuits in vivo . In this study, Nagai et al., report and carefully validate a genetic approach to attenuate astrocyte G q GPCR signaling in the mouse brain in vivo with consequential effects on mouse behavior. The use of the method will enable new types of experiments in order to explore astrocytic contributions to neural circuit function and behavior and will be applicable broadly to open questions in neuroscience as well as in glial biology.