Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels
Publication date: 17/02/2026
Authors: DeMeulenaere KE, Grant RA, Megan E. Martin ME, Hiam A. Valencia HA, Radulovic J, Salter MW, Prakriya M
Journal: Science Signaling
Commentary: In this study, DeMeulenaere et al. uncover a central role for the calcium channel Orai1 in shaping microglial reactivity and its behavioral consequences. By selectively deleting Orai1 in microglia, the authors show that this channel is essential for store-operated calcium entry and for sustaining a robust proinflammatory response. Loss of Orai1 profoundly alters microglial identity. Transcriptomic analyses reveal a marked suppression of canonical inflammatory pathways, including IFN, TNF, NF-κB, and IL-6–JAK/STAT3 signaling. At the same time, Orai1-deficient microglia increase expression of genes linked to neuroprotection and repair, such as Bdnf, Arg1, and Pparg. This shift is not only transcriptional but also metabolic. Metabolomic profiling indeed shows reduced TCA cycle intermediates alongside increased NAD⁺, AMP, and itaconate, metabolic signatures associated with anti-inflammatory and stress-adaptive programs. Together, these data suggest that Orai1 acts as a key node coupling calcium influx to inflammatory and metabolic reprogramming. Crucially, the in vitro findings translate into in vivo findings. After systemic LPS administration, a well-established model of inflammation-induced motivational dysfunction, microglial Orai1 knockout mice exhibit attenuated microglial and astrocytic reactivity and reduced hippocampal levels of IL-1β and IL-6. Also, these molecular and cellular changes translate into behavioral resilience: Orai1-deficient mice are protected from LPS-induced impairments in reward-seeking and escape behaviors, paradigms commonly used to model anhedonia and helplessness. This study positions Orai1 as a molecular switch controlling microglial state transitions. By linking calcium signaling to immunometabolic remodeling and behavioral outcomes, it provides a mechanistic framework with clear implications for neuroinflammatory and neuropsychiatric disorders where maladaptive microglial activation contributes to symptom progression.
Commented by: Luigi Balasco
DOI: 10.1126/scisignal.ady8398
