Specific and behaviorally consequential astrocyte G(q) GPCR signaling attenuation in vivo with i beta ARK

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 beta-adrenergic receptor kinase 1 (i beta ARK; and inactive D110A control) to attenuate astrocyte G(q) GPCR signaling. i beta ARK significantly attenuated G(q) GPCR Ca2+ signaling in brain slices and, in vivo, altered behavioral responses, spared other GPCR responses, and did not alter astrocyte spontaneous Ca2+ signals, morphology, electrophysiological properties, or gene expression in the striatum. Furthermore, brain-wide attenuation of astrocyte G(q) GPCR signaling with i beta ARK using PHP.eB adeno-associated viruses (AAVs), when combined with c-Fos mapping, suggested nuclei-specific contributions to behavioral adaptation and spatial memory. i beta ARK extends the toolkit needed to explore functions of astrocyte G(q) GPCR signaling within neural circuits in vivo.