# Regulation of microglia-mediated neuroinflammation by store operated Orai1 channels

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2021 · $438,473

## Abstract

Microglia are the tissue resident macrophage-like cells in the central nervous system that regulate
numerous physiological functions ranging from phagocytosis, detection of brain injuries, and
synaptic pruning. Growing evidence indicates that microglia also play powerful roles in regulating
neuronal excitability and synaptic transmission by secreting a variety of neuroactive factors
especially proinflammatory cytokines. These cytokines evoke a vast array of effects on neurons
and glia including alterations in Ca2+ signaling and synaptic transmission, which are implicated in
brain pathologies such as neuropathic pain. In particular, following nerve injury, microglia rapidly
produce TNFa, IL1b , and the growth factor, BDNF, which enhance the strength of excitatory
synaptic transmission in nociceptive circuits of the spinal cord to induce neuropathic pain.
However, the checkpoints that regulate the production and release of inflammatory mediators from
microglia are not well-understood. Our preliminary results indicate that store-operated Orai1
channels are a major mechanism for purinergic-evoked Ca2+ signals in microglia and their opening
stimulates the induction and release of TNFa and IL1b. Based on this evidence, we hypothesize
that Orai1 channels are essential regulators of microglia-mediated neuroinflammation in the
context of neuropathic pain. We propose three specific aims to test this hypothesis: 1) Define the
role of Orai1 channels for ATP-evoked Ca2+ signals and the inflammatory output of microglia, 2)
Determine the effects of Orai1 channel-mediated secretion of proinflammatory mediators on
synaptic transmission in the dorsal horn of the spinal cord following nerve injury, and 3) examine
the in vivo relevance of Orai1 channel-mediated inflammatory cytokine production from microglia in
a model of neuropathic pain. We will approach these questions using a newly created microglia-specific inducible Orai1 KO mouse and Ca2+ imaging, slice electrophysiology, and behavioral
analysis. Results from these studies will advance our understanding of the physiological role of
Orai1 channels for regulating microglia-mediated neuroinflammation and aid the quest for
developing new microglial-targeted therapies for pathological diseases affecting brain function.

## Key facts

- **NIH application ID:** 10235416
- **Project number:** 1R21NS122347-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Murali Prakriya
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,473
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235416

## Citation

> US National Institutes of Health, RePORTER application 10235416, Regulation of microglia-mediated neuroinflammation by store operated Orai1 channels (1R21NS122347-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10235416. Licensed CC0.

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