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

Nagai, Jun and Bellafard, Arash and Qu, Zhen and Yu, Xinzhu and Ollivier, Matthias and Gangwani, Mohitkumar R. and Diaz-Castro, Blanca and Coppola, Giovanni and Schumacher, Sarah M. and Golshani, Peyman and Gradinaru, Viviana and Khakh, Baljit S. (2021) Specific and behaviorally consequential astrocyte G_q GPCR signaling attenuation in vivo with iβARK. Neuron, 109 (14). pp. 2256-2274. ISSN 0896-6273. PMCID PMC8418870. doi:10.1016/j.neuron.2021.05.023.

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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 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 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 G_q GPCR signaling within neural circuits in vivo.

Item Type:Article
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URLURL TypeDescription CentralArticle
Coppola, Giovanni0000-0003-2105-1061
Gradinaru, Viviana0000-0001-5868-348X
Alternate Title:Specific and behaviorally consequential astrocyte Gq GPCR signaling attenuation in vivo with iβARK
Additional Information:© 2021 Elsevier Inc. Received 20 November 2020, Revised 14 April 2021, Accepted 18 May 2021, Available online 16 June 2021. We thank the UCLA Neuroscience Genomics Core for assistance with sequencing and Fuying Gao for helping with data analysis. Thanks to UCLA Behavioral Testing Core for guidance and equipment. Collaborations between the B.S.K. and V.G. groups are supported by National Institutes of Health (NIH) grant DA047444. This work was supported by NIH grant R35NS111583, an Allen Distinguished Investigator Award through the Paul G. Allen Frontiers Group, and the Ressler Family Foundation (B.S.K.). S.M.S. was supported by the Brody Family Medical Trust Fund Fellowship and NIH grant HL132882. J.N. was partly supported by a JSPS Overseas Research Fellowship (H28-729) and the Uehara Memorial Foundation Overseas Postdoctoral Research Fellowship (201730082). X.Y. was partly supported by the American Heart Association (16POST27260256). We acknowledge support from the NINDS Informatics Center for Neurogenetics and Neurogenomics (grant P30 NS062691 to G.C.) and the Genetics, Genomics and Informatics Core of the Semel Institute of Neuroscience at UCLA (grant U54HD087101-01 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development). P.G. and A.B. were supported by NIH grant R01NS116589. V.G. was supported by a NIH Pioneer Award (DP1OD025535), the Vallee Foundation, the CZI Neurodegeneration Challenge Network, and the Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research (CLOVER) for technology development and dissemination. Author contributions: J.N. carried out most of the experiments, including molecular biology, mouse surgeries, IHC, slice imaging, RNA-seq, and behavior, with help from X.Y. and B.D.-C. X.Y. performed analyses of RNA-seq. A.B. performed in vivo cortical calcium imaging experiments, including those surgeries. Z.Q. generated the AAV-PHP.eB viruses with guidance from V.G., who provided equipment. S.M.S. discussed iβARK with B.S.K. at the germinal stages and shared reagents and insights. M.O. and M.R.G. helped with revision experiments. G.C. provided guidance on the analysis of RNA-seq data. P.G. supervised the in vivo imaging experiments. B.S.K. conceived, designed, and directed the project; guided analyses; and performed electrophysiology. B.S.K. and J.N. wrote the paper, and all authors commented. The authors declare no competing interests relevant to this study. However, B.S.K. is a consultant for Third Rock Ventures.
Funding AgencyGrant Number
Paul G. Allen Family FoundationUNSPECIFIED
Ressler Family FoundationUNSPECIFIED
Brody Family Medical Trust FundUNSPECIFIED
Japan Society for the Promotion of Science (JSPS)H28-729
Uehara Memorial Foundation201730082
American Heart Association16POST27260256
NIHP30 NS062691
Vallee FoundationUNSPECIFIED
CZI Neurodegeneration Challenge NetworkUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Subject Keywords:GPCR; Gq; astrocyte; behavior; signaling; silencing; calcium; AAV; spatial memory; behavioral adaptation
Issue or Number:14
PubMed Central ID:PMC8418870
Record Number:CaltechAUTHORS:20210625-220915439
Persistent URL:
Official Citation: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, Specific and behaviorally consequential astrocyte Gq GPCR signaling attenuation in vivo with iβARK, Neuron, Volume 109, Issue 14, 2021, Pages 2256-2274.e9, ISSN 0896-6273,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109586
Deposited By: Tony Diaz
Deposited On:25 Jun 2021 22:22
Last Modified:29 Jul 2022 18:26

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