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

Author

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  • Michaela M. Novakovic

    (Northwestern University Feinberg School of Medicine)

  • Kirill S. Korshunov

    (Northwestern University Feinberg School of Medicine)

  • Rogan A. Grant

    (Northwestern University Feinberg School of Medicine)

  • Megan E. Martin

    (Northwestern University Feinberg School of Medicine)

  • Hiam A. Valencia

    (Northwestern University Feinberg School of Medicine)

  • G. R. Scott Budinger

    (Northwestern University Feinberg School of Medicine)

  • Jelena Radulovic

    (Albert Einstein School of Medicine)

  • Murali Prakriya

    (Northwestern University Feinberg School of Medicine
    Northwestern University Feinberg School of Medicine)

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.

Suggested Citation

  • Michaela M. Novakovic & Kirill S. Korshunov & Rogan A. Grant & Megan E. Martin & Hiam A. Valencia & G. R. Scott Budinger & Jelena Radulovic & Murali Prakriya, 2023. "Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40968-6
    DOI: 10.1038/s41467-023-40968-6
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    1. Shane A. Liddelow & Kevin A. Guttenplan & Laura E. Clarke & Frederick C. Bennett & Christopher J. Bohlen & Lucas Schirmer & Mariko L. Bennett & Alexandra E. Münch & Won-Suk Chung & Todd C. Peterson & , 2017. "Neurotoxic reactive astrocytes are induced by activated microglia," Nature, Nature, vol. 541(7638), pages 481-487, January.
    2. Andrea Delekate & Martina Füchtemeier & Toni Schumacher & Cordula Ulbrich & Marco Foddis & Gabor C. Petzold, 2014. "Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
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    1. Qilin Guo & Davide Gobbo & Na Zhao & Hong Zhang & Nana-Oye Awuku & Qing Liu & Li-Pao Fang & Tanja M. Gampfer & Markus R. Meyer & Renping Zhao & Xianshu Bai & Shan Bian & Anja Scheller & Frank Kirchhof, 2024. "Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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