Published on: Mar 12, 2026
Scientists at Northwestern Medicine have identified a crucial mechanism by which calcium signaling channels in microglia the brain’s primary immune cells regulate neuroinflammation and influence behaviors linked to affective mood disorders. The findings, reported in a recent study, highlight the potential of targeting Orai1 calcium channels to modulate chronic neuroinflammatory responses and develop new therapeutic strategies for neurological and psychiatric conditions.
Microglia play a central role in maintaining brain health by responding to injury and disease. They can shift between homeostatic and reactive states to either suppress or promote inflammation within the central nervous system. However, the molecular processes governing these cellular transitions have remained poorly understood.
To address this gap, researchers led by Murali Prakriya investigated how calcium (Ca²⁺) signaling contributes to microglial state regulation and inflammatory signaling. Previous work from the group demonstrated that Orai1-mediated calcium entry is critical for multiple intracellular functions, including gene regulation, immune responses, and phagocytosis.
In the present study, the team employed integrated transcriptomic, metabolomic, and in vivo functional analyses using mouse models of central nervous system inflammation. Their results revealed that Orai1 calcium channels are essential for enabling microglia to adopt a reactive, pro-inflammatory phenotype. These channels were shown to control the expression of genes associated with immune activation, inflammatory pathways, and cellular metabolism.
Notably, microglia lacking Orai1 failed to transition into a pro-inflammatory state. Instead, these cells exhibited an anti-inflammatory and neuroprotective profile, characterized by increased production of molecules such as brain-derived neurotrophic factor (BDNF), which supports neuronal survival and growth. Genetic deletion of Orai1 also reduced inflammatory responses in both microglia and astrocytes and lowered levels of key pro-inflammatory cytokines, including interleukin-1β and interleukin-6, particularly in the hippocampus.
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