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 and Murali Prakriya ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40968-6

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