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Microglial reactivity and neuroinflammation-driven in motivational behaviors are regulated by Orai1 channels

ABSTRACT: Microglia are the primary immune cells of the central nervous system (CNS) and act as the first line of defense against disease and injury in the brain by releasing inflammatory molecules and clearing dead cells. Microglial functions are tightly regulated by dynamic transitions between homeostatic and reactive cell states, which can either exacerbate or resolve CNS inflammation. While Ca2+ signaling is known to regulate specific microglial functions such as phagocytosis, its role in controlling these critical state transitions remains poorly understood. Here, we identify the Orai1 Ca2+ channel as a key regulator of microglial plasticity and inflammation-induced behavioral dysfunction in mice. Transcriptomic and metabolomic analyses revealed that conditional Orai1 deletion in microglia suppressed proinflammatory programs linked to immunity and inflammation. Conversely, Orai1 knockout increased expression of growth factors and anti-inflammatory mediators, including BDNF, ARG1, and the mitochondrial metabolite, itaconate. In a model of CNS inflammation induced by peripheral inflammatory challenge with lipopolysaccharide (LPS), Orai1 deficiency attenuated microglial and astrocyte reactivity and reduced hippocampal levels of the cytokines IL-1β and IL-6. Consistent with these cellular changes, microglial Orai1 knockout mice were protected against LPS-induced changes in motivational, depression-like behaviors, including impairments in reward-seeking and escape responses. These findings establish Orai1 channels as central regulators of microglial cell plasticity and neuroimmune responses, highlighting their therapeutic potential for neuroinflammatory disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE310141 | GEO | 2025/11/24

REPOSITORIES: GEO

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Project description:Microglia colonize the brain parenchyma at early stages of development and accumulate in specific regions where they actively participate in cell death, angiogenesis, neurogenesis and synapse elimination. A recurring feature of embryonic microglial distribution is their association with developing axon tracts which, together with in vitro data, supports the idea of a physiological role for microglia in neurite development. Yet the demonstration of this role of microglia is still lacking. Here, we have studied the consequences of microglial dysfunction on the formation of the corpus callosum, the largest connective structure in the mammalian brain, which shows consistent microglial accumulation during development. We studied two models of microglial dysfunction: the loss-of-function of DAP12, a key microglial-specific signaling molecule, and a model of maternal inflammation by peritoneal injection of LPS at E15.5. We performed transcriptional profiling of maternally inflamed and Dap12-mutant microglia at E17.5. We found that both treatments principally down-regulated genes involved in nervous system development and function, particularly in neurite formation. We then analyzed the functional consequences of these microglial dysfunctions on the formation of the corpus callosum. We also took advantage of the Pu.1-/- mouse line, which is devoid of microglia. We now show that all three models of altered microglial activity resulted in the same defasciculation phenotype. Our study demonstrates that microglia are actively involved in the fasciculation of corpus callosum axons. To investigate possible roles for microglial during brain development, we challenged microglial function by two complementary approaches. First, we induced maternal inflammation by peritoneal injection of LPS into pregnant dams. Next, we analyzed the consequences of a loss of function of DAP12, a signaling molecule specifically expressed in microglia that is crucial for several aspects of microglia biology (references in Wakselman et al., 2008). We compared the gene expression profiles of microglia from control, maternally-inflamed by LPS (MI), and Dap12-mutated embryos. We isolated RNA from FACS sorted maternally inflamed (by LPS) and Dap12-mutant microglia at E17.5 pooled per pregnant dam; as a control we included PBS treated and untreated (UT) microglia. We compared gene expression between maternally inflamed microlgia (PBSvsLPS) and DAP12-mutant microglia (UTvsDAP12KO).

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Microglial reactivity and neuroinflammation-driven in motivational behaviors are regulated by Orai1 channels

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