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Regulation of neuropathic pain by microglial Orai1 channels.

ABSTRACT: Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca²⁺ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation in the dorsal horn, spinal cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in microglial Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.

SUBMITTER: Tsujikawa S

PROVIDER: S-EPMC9883051 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Regulation of neuropathic pain by microglial Orai1 channels.

Tsujikawa Shogo S DeMeulenaere Kaitlyn E KE Centeno Maria V MV Ghazisaeidi Shahrzad S Martin Megan E ME Tapies Martinna R MR Maneshi Mohammad M MM Yamashita Megumi M Stauderman Kenneth A KA Apkarian Apkar V AV Salter Michael W MW Prakriya Murali M

Science advances 20230127 4

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca<sup>2+</sup> signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial ...[more]

PMID: 36706180

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Project description:Key pointsTemporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca2+ signalling in many aspects of epilepsy but the diversity of Ca2+ channels that regulate this syndrome are not well-understood. Here, we report that mice lacking the store-operated Ca2+ channel, Orai1, in the brain show markedly stronger seizures in response to the chemoconvulsants, kainic acid and pilocarpine. Electrophysiological analysis reveals that selective deletion of Orai1 channels in inhibitory neurons disables chemoconvulsant-induced excitation of GABAergic neurons in the CA1 hippocampus. Likewise, deletion of Orai1 in GABAergic neurons abrogates the chemoconvulsant-induced burst of spontaneous inhibitory postsynaptic currents (sIPSCs) on CA1 pyramidal neurons in the hippocampus. This loss of chemoconvulsant inhibition likely aggravates status epilepticus in Orai1 KO mice. These results identify Orai1 channels as regulators of hippocampal interneuron excitability and seizures.AbstractStore-operated Orai1 channels are a major mechanism for Ca2+ entry in many cells and mediate numerous functions including gene expression, cytokine production and gliotransmitter release. Orai1 is expressed in many regions of the mammalian brain; however, its role in regulating neuronal excitability, synaptic function and brain disorders has only now begun to be investigated. To investigate a potential role of Orai1 channels in status epilepticus induced by chemoconvulsants, we examined acute seizures evoked by intraperitoneal injections of kainic acid (KA) and pilocarpine in mice with a conditional deletion of Orai1 (or its activator STIM1) in the brain. Brain-specific Orai1 and STIM1 knockout (KO) mice exhibited significantly stronger seizures (P = 0.00003 and P < 0.00001), and higher chemoconvulsant-induced mortality (P = 0.02) compared with wildtype (WT) littermates. Electrophysiological recordings in hippocampal brain slices revealed that KA stimulated the activity of inhibitory interneurons in the CA1 hippocampus (P = 0.04) which failed to occur in Orai1 KO mice. Further, KA and pilocarpine increased the frequency of spontaneous IPSCs in CA1 pyramidal neurons >twofold (KA: P = 0.04; pilocarpine: P = 0.0002) which was abolished in Orai1 KO mice. Mice with selective deletion of Orai1 in GABAergic neurons alone also showed stronger seizures to KA (P = 0.001) and pilocarpine (P < 0.00001) and loss of chemoconvulsant-induced increases in sIPSC responses compared with WT controls. We conclude that Orai1 channels regulate chemoconvulsant-induced excitation in GABAergic neurons and that destabilization of the excitatory/inhibitory balance in Orai1 KO mice aggravates chemoconvulsant-mediated seizures. These results identify Orai1 channels as novel molecular regulators of hippocampal neuronal excitability and seizures.

Dataset Information

Regulation of neuropathic pain by microglial Orai1 channels.

Publications

Regulation of neuropathic pain by microglial Orai1 channels.

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