G i/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission

Caitlin A. Durkee, Ana Covelo, Justin Lines, Paulo Kofuji, Juan Aguilar, Alfonso Araque

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

G protein-coupled receptors (GPCRs) play key roles in intercellular signaling in the brain. Their effects on cellular function have been largely studied in neurons, but their functional consequences on astrocytes are less known. Using both endogenous and chemogenetic approaches with DREADDs, we have investigated the effects of G q and G i/o GPCR activation on astroglial Ca 2+ -based activity, gliotransmitter release, and the functional consequences on neuronal electrical activity. We found that while G q GPCR activation led to cellular activation in both neurons and astrocytes, G i/o GPCR activation led to cellular inhibition in neurons and cellular activation in astrocytes. Astroglial activation by either G q or G i/o protein-mediated signaling stimulated gliotransmitter release, which increased neuronal excitability. Additionally, activation of G q and G i/o DREADDs in vivo increased astrocyte Ca 2+ activity and modified neuronal network electrical activity. Present results reveal additional complexity of the signaling consequences of excitatory and inhibitory neurotransmitters in astroglia-neuron network operation and brain function.

Original languageEnglish (US)
Pages (from-to)1076-1093
Number of pages18
JournalGlia
Volume67
Issue number6
DOIs
StatePublished - Jun 2019

Bibliographical note

Funding Information:
We would like to thank Ruth Quintana, Stephanie Nistler, and Heidi Busch for technical support; Mario Martin-Fernandez, and Michelle Corkrum for helpful suggestions; Mark Sanders, Guillermo Marques and Jason Mitchell at the University of Minnesota – University Imaging Centers for assistance using the Leica SP5 Multiphoton Confocal Upright Microscope; The MnDRIVE Optogenetics Core at the University of Minnesota for technical support; Viral vectors used in this study were prepared by the University of Minnesota Viral Vector and Cloning Core; Ju Chen for generously donating the IP3R2−/− mice; Dwight Bergles and Amit Agarwal for generously donating the GLAST-CreERT2xR26-lsl-GCaMP3 mice; and the UNC Vector Core for providing the DREADDs viruses. This work was supported by National Institutes of Health-NINDS (R01NS097312-01) and Human Frontier Science Program (Research Grant RGP0036/2014) to A.A and NIH-NINDS (5 F31 NS 93751-3) to C.A.D and NIH-NIA (1F31 AG057155-01A1) to J.L.. The authors declare no competing financial interests.

Funding Information:
information National Institutes of Health, Grant/Award Numbers: R01NS097312, R01NS108686, F31AG057155-01A1, F31NS093751; Human Frontier Science Program, Grant/Award Number: RGP0036/2014 We would like to thank Ruth Quintana, Stephanie Nistler, and Heidi Busch for technical support; Mario Martin-Fernandez, and Michelle Corkrum for helpful suggestions; Mark Sanders, Guillermo Marques and Jason Mitchell at the University of Minnesota ? University Imaging Centers for assistance using the Leica SP5 Multiphoton Confocal Upright Microscope; The MnDRIVE Optogenetics Core at the University of Minnesota for technical support; Viral vectors used in this study were prepared by the University of Minnesota Viral Vector and Cloning Core; Ju Chen for generously donating the IP3R2?/? mice; Dwight Bergles and Amit Agarwal for generously donating the GLAST-CreERT2xR26-lsl-GCaMP3 mice; and the UNC Vector Core for providing the DREADDs viruses. This work was supported by National Institutes of Health-NINDS (R01NS097312-01) and Human Frontier Science Program (Research Grant RGP0036/2014) to A.A and NIH-NINDS (5 F31 NS 93751-3) to C.A.D and NIH-NIA (1F31 AG057155-01A1) to J.L. The authors declare no competing financial interests.

Keywords

  • DREADDs
  • G protein-coupled receptors
  • astrocyte Ca
  • astrocytes
  • gliotransmission

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