Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels

Michaela M. Novakovic; Kirill S. Korshunov; Rogan A. Grant; Megan E. Martin; Hiam A. Valencia; G. R.Scott Budinger; Jelena Radulovic; Murali Prakriya

doi:10.1038/s41467-023-40968-6

Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels

Michaela M. Novakovic, Kirill S. Korshunov, Rogan A. Grant, Megan E. Martin, Hiam A. Valencia, G. R.Scott Budinger, Jelena Radulovic, Murali Prakriya^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

Astrocytes contribute to brain inflammation in neurological disorders but the molecular mechanisms controlling astrocyte reactivity and their relationship to neuroinflammatory endpoints are complex and poorly understood. In this study, we assessed the role of the calcium channel, Orai1, for astrocyte reactivity and inflammation-evoked depression behaviors in mice. Transcriptomics and metabolomics analysis indicated that deletion of Orai1 in astrocytes downregulates genes in inflammation and immunity, metabolism, and cell cycle pathways, and reduces cellular metabolites and ATP production. Systemic inflammation by peripheral lipopolysaccharide (LPS) increases hippocampal inflammatory markers in WT but not in astrocyte Orai1 knockout mice. Loss of Orai1 also blunts inflammation-induced astrocyte Ca²⁺ signaling and inhibitory neurotransmission in the hippocampus. In line with these cellular changes, Orai1 knockout mice showed amelioration of LPS-evoked depression-like behaviors including anhedonia and helplessness. These findings identify Orai1 as an important signaling hub controlling astrocyte reactivity and astrocyte-mediated brain inflammation that is commonly observed in many neurological disorders.

Original language	English (US)
Article number	5500
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40968-6
State	Published - Dec 2023

Funding

We thank members of the Prakriya laboratory for helpful discussions and Dr. Mohamed Trebak and Dr. Gabriela Piso for their comments on the manuscript. Metabolomics services were provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We thank Yuliya Politanska in the Pulmonary RNA-seq core for assistance with the preparation and processing of the RNA samples, and Dr. Mark Dell’Acqua (U of Colorado) for GFP-NFATc3. Figure schematics were developed using BioRender.com. This work was supported by NIH grants R01NS057499 and R35NS132349 to MP, P01AG049665 and R01HL158139 to GRSB, and R01MH108837 to JR. MMN was supported by the predoctoral training grant T32 AG020506. RAG was supported by a predoctoral NIH NRSA, F31AG071225. We thank members of the Prakriya laboratory for helpful discussions and Dr. Mohamed Trebak and Dr. Gabriela Piso for their comments on the manuscript. Metabolomics services were provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We thank Yuliya Politanska in the Pulmonary RNA-seq core for assistance with the preparation and processing of the RNA samples, and Dr. Mark Dell’Acqua (U of Colorado) for GFP-NFATc3. Figure schematics were developed using BioRender.com. This work was supported by NIH grants R01NS057499 and R35NS132349 to MP, P01AG049665 and R01HL158139 to GRSB, and R01MH108837 to JR. MMN was supported by the predoctoral training grant T32 AG020506. RAG was supported by a predoctoral NIH NRSA, F31AG071225.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-40968-6

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title = "Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels",

abstract = "Astrocytes contribute to brain inflammation in neurological disorders but the molecular mechanisms controlling astrocyte reactivity and their relationship to neuroinflammatory endpoints are complex and poorly understood. In this study, we assessed the role of the calcium channel, Orai1, for astrocyte reactivity and inflammation-evoked depression behaviors in mice. Transcriptomics and metabolomics analysis indicated that deletion of Orai1 in astrocytes downregulates genes in inflammation and immunity, metabolism, and cell cycle pathways, and reduces cellular metabolites and ATP production. Systemic inflammation by peripheral lipopolysaccharide (LPS) increases hippocampal inflammatory markers in WT but not in astrocyte Orai1 knockout mice. Loss of Orai1 also blunts inflammation-induced astrocyte Ca2+ signaling and inhibitory neurotransmission in the hippocampus. In line with these cellular changes, Orai1 knockout mice showed amelioration of LPS-evoked depression-like behaviors including anhedonia and helplessness. These findings identify Orai1 as an important signaling hub controlling astrocyte reactivity and astrocyte-mediated brain inflammation that is commonly observed in many neurological disorders.",

author = "Novakovic, {Michaela M.} and Korshunov, {Kirill S.} and Grant, {Rogan A.} and Martin, {Megan E.} and Valencia, {Hiam A.} and Budinger, {G. R.Scott} and Jelena Radulovic and Murali Prakriya",

note = "Funding Information: We thank members of the Prakriya laboratory for helpful discussions and Dr. Mohamed Trebak and Dr. Gabriela Piso for their comments on the manuscript. Metabolomics services were provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We thank Yuliya Politanska in the Pulmonary RNA-seq core for assistance with the preparation and processing of the RNA samples, and Dr. Mark Dell{\textquoteright}Acqua (U of Colorado) for GFP-NFATc3. Figure schematics were developed using BioRender.com. This work was supported by NIH grants R01NS057499 and R35NS132349 to MP, P01AG049665 and R01HL158139 to GRSB, and R01MH108837 to JR. MMN was supported by the predoctoral training grant T32 AG020506. RAG was supported by a predoctoral NIH NRSA, F31AG071225. Funding Information: We thank members of the Prakriya laboratory for helpful discussions and Dr. Mohamed Trebak and Dr. Gabriela Piso for their comments on the manuscript. Metabolomics services were provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We thank Yuliya Politanska in the Pulmonary RNA-seq core for assistance with the preparation and processing of the RNA samples, and Dr. Mark Dell{\textquoteright}Acqua (U of Colorado) for GFP-NFATc3. Figure schematics were developed using BioRender.com. This work was supported by NIH grants R01NS057499 and R35NS132349 to MP, P01AG049665 and R01HL158139 to GRSB, and R01MH108837 to JR. MMN was supported by the predoctoral training grant T32 AG020506. RAG was supported by a predoctoral NIH NRSA, F31AG071225. Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-40968-6",

language = "English (US)",

volume = "14",

journal = "Nature communications",

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T1 - Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels

AU - Novakovic, Michaela M.

AU - Korshunov, Kirill S.

AU - Grant, Rogan A.

AU - Martin, Megan E.

AU - Valencia, Hiam A.

AU - Budinger, G. R.Scott

AU - Radulovic, Jelena

AU - Prakriya, Murali

N1 - Funding Information: We thank members of the Prakriya laboratory for helpful discussions and Dr. Mohamed Trebak and Dr. Gabriela Piso for their comments on the manuscript. Metabolomics services were provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We thank Yuliya Politanska in the Pulmonary RNA-seq core for assistance with the preparation and processing of the RNA samples, and Dr. Mark Dell’Acqua (U of Colorado) for GFP-NFATc3. Figure schematics were developed using BioRender.com. This work was supported by NIH grants R01NS057499 and R35NS132349 to MP, P01AG049665 and R01HL158139 to GRSB, and R01MH108837 to JR. MMN was supported by the predoctoral training grant T32 AG020506. RAG was supported by a predoctoral NIH NRSA, F31AG071225. Funding Information: We thank members of the Prakriya laboratory for helpful discussions and Dr. Mohamed Trebak and Dr. Gabriela Piso for their comments on the manuscript. Metabolomics services were provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We thank Yuliya Politanska in the Pulmonary RNA-seq core for assistance with the preparation and processing of the RNA samples, and Dr. Mark Dell’Acqua (U of Colorado) for GFP-NFATc3. Figure schematics were developed using BioRender.com. This work was supported by NIH grants R01NS057499 and R35NS132349 to MP, P01AG049665 and R01HL158139 to GRSB, and R01MH108837 to JR. MMN was supported by the predoctoral training grant T32 AG020506. RAG was supported by a predoctoral NIH NRSA, F31AG071225. Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023/12

Y1 - 2023/12

N2 - Astrocytes contribute to brain inflammation in neurological disorders but the molecular mechanisms controlling astrocyte reactivity and their relationship to neuroinflammatory endpoints are complex and poorly understood. In this study, we assessed the role of the calcium channel, Orai1, for astrocyte reactivity and inflammation-evoked depression behaviors in mice. Transcriptomics and metabolomics analysis indicated that deletion of Orai1 in astrocytes downregulates genes in inflammation and immunity, metabolism, and cell cycle pathways, and reduces cellular metabolites and ATP production. Systemic inflammation by peripheral lipopolysaccharide (LPS) increases hippocampal inflammatory markers in WT but not in astrocyte Orai1 knockout mice. Loss of Orai1 also blunts inflammation-induced astrocyte Ca2+ signaling and inhibitory neurotransmission in the hippocampus. In line with these cellular changes, Orai1 knockout mice showed amelioration of LPS-evoked depression-like behaviors including anhedonia and helplessness. These findings identify Orai1 as an important signaling hub controlling astrocyte reactivity and astrocyte-mediated brain inflammation that is commonly observed in many neurological disorders.

AB - Astrocytes contribute to brain inflammation in neurological disorders but the molecular mechanisms controlling astrocyte reactivity and their relationship to neuroinflammatory endpoints are complex and poorly understood. In this study, we assessed the role of the calcium channel, Orai1, for astrocyte reactivity and inflammation-evoked depression behaviors in mice. Transcriptomics and metabolomics analysis indicated that deletion of Orai1 in astrocytes downregulates genes in inflammation and immunity, metabolism, and cell cycle pathways, and reduces cellular metabolites and ATP production. Systemic inflammation by peripheral lipopolysaccharide (LPS) increases hippocampal inflammatory markers in WT but not in astrocyte Orai1 knockout mice. Loss of Orai1 also blunts inflammation-induced astrocyte Ca2+ signaling and inhibitory neurotransmission in the hippocampus. In line with these cellular changes, Orai1 knockout mice showed amelioration of LPS-evoked depression-like behaviors including anhedonia and helplessness. These findings identify Orai1 as an important signaling hub controlling astrocyte reactivity and astrocyte-mediated brain inflammation that is commonly observed in many neurological disorders.

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Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels

Abstract

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