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

Jun Nagai, Arash Bellafard, Zhe Qu, Xinzhu Yu, Matthias Ollivier, Mohitkumar R. Gangwani, Blanca Diaz-Castro, Giovanni Coppola, Sarah M. Schumacher, Peyman Golshani, Viviana Gradinaru, Baljit S. Khakh

Research output: Contribution to journalArticlepeer-review

Abstract

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 Gq 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 Gq GPCR signaling. iβARK significantly attenuated Gq 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 Gq GPCR signaling with iβARK using PHP.eB adeno-associated viruses (AAVs), when combined with c-Fos mapping, suggested nuclei-specific contributions to behavioral adaptation and spatial memory. iβARK extends the toolkit needed to explore functions of astrocyte Gq GPCR signaling within neural circuits in vivo.

Original languageEnglish (US)
Pages (from-to)2256-2274.e9
JournalNeuron
Volume109
Issue number14
DOIs
StatePublished - Jul 21 2021

Keywords

  • AAV
  • GPCR
  • Gq
  • astrocyte
  • behavior
  • behavioral adaptation
  • calcium
  • signaling
  • silencing
  • spatial memory

ASJC Scopus subject areas

  • Neuroscience(all)

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