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How microglia sense and regulate neuronal activity
Open accessAbstract
Microglia are innate immune cells of the central nervous system that sense extracellular cues. Brain injuries, inflammation, and pathology evoke dynamic structural responses in microglia, altering their morphology and motility. The dynamic motility of microglia is hypothesized to be a critical first step in sensing local alterations and engaging in pattern-specific responses. Alongside their pathological responses, microglia also sense and regulate neuronal activity. In this review, we consider the extracellular molecules, receptors, and mechanisms that allow microglia to sense neuronal activity changes under both hypoactivity and hyperactivity. We also highlight emerging in vivo evidence that microglia regulate neuronal activity, ranging from physiological to pathophysiological conditions. In addition, we discuss the emerging role of calcium signaling in microglial responses to the extracellular environment. The dynamic function of microglia in monitoring and influencing neuronal activity may be critical for brain homeostasis and circuit modification in health and disease.
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“Ca2+ currents have also been implicated in the regulation of microglial motility (reviewed in [50]).”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [50]
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León‐Rodríguez, A., Fernández‐Arjona, M. D. M., Pedraza, C., López‐Aranda, M. F., Visser, R., & López-Ávalos, M. D. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1828445 · Cited by 1
Hu, Y., Chen, H., Zhao, J., Wang, J., Chen, J., Luo, W., & Zhang, J. (2026) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2026.143120 · Cited by 1
Mordelt, A., Schuurmans, I. M. E., Scheefhals, N., Hommersom, M. P., Slottje, K., Mast, K., Graziani, M., González, C. O., Mulder, K. W., Wingens, L., et al. (2026) · Stem Cell Reports · doi:10.1016/j.stemcr.2026.103053 · Cited by 5
Contactomics of Microglia and Intercellular Communication
Cserép, C., Pósfai, B., Szabadits, E., & Dénes, Á. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_8 · Cited by 1
McGregor, B. A., Raihan, M. O., Brishti, A., Hur, J., & Porter, J. E. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1544971 · Cited by 1
Xathine unveiled: Bridging CD4+ T cell and stress-induced disorders through purine metabolism
Zhang, L., Dong, J.-X., Li, Y., & Jin, J. (2025) · Brain Behavior and Immunity Integrative · doi:10.1016/j.bbii.2025.100113 · Cited by 1
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Eyal, S. (2021) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597211004568 · Cited by 1
Mattei, D., Ivanov, A., Hammer, J., Ugursu, B., Schalbetter, S. M., Richetto, J., Weber‐Stadlbauer, U., Mueller, F. S., Scarborough, J., Wolf, S. A., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.17.567571 · Cited by 1
Neuronal activity promotes repair by microglial reprogramming following demyelinationPreprint
Perrot, C., Ronzano, R., Li, Z., Aigrot, M., Pantazou, V., Stheneur, P., Lejeune, F., Zalc, B., Quintana, F. J., Stankoff, B., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.19.689194 · Cited by 2
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Liang, Y., Shi, W., Dale, E. M., Zhao, S., Qi, F., Haruwaka, K., Hou, Q., Fei, M., Harris, L., Hua, X., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.26.696634 · Cited by 1
Self-citationTHIK-1 channel mediates microglial glucose sensing and modulates AgRP neuronsPreprint
Liu, Q., Bean, J. C., Jian, J., Zhou, T., Yang, Y., Sun, M., Li, Y., Conde, K., Wang, M., Deng, Y., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.15.699765 · Cited by 1
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Mordelt, A., Scheefhals, N., Schuurmans, I. M. E., Slottje, K., Rivera, M. C., Hommersom, M. P., Huang, A., Bichmann, L., Lewerissa, E., van Hugte, E., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.04.703799 · Cited by 1
Song, J., Lou, J., Jiang, C. Q., Bai, H., Chen, S., & Xing, Y. (2023) · Research Square · doi:10.21203/rs.3.rs-2453080/v1
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JingjingSong, JiyuLou, ChaoJiang, HongyingBai, SiChen, & YuanyuanXing (2023) · Research Square · doi:10.21203/rs.3.rs-2471501/v1
Choi, S., Hill, D., Young, J., & Cordeiro, M. F. (2023) · Methods in cell biology · doi:10.1016/bs.mcb.2022.12.008
Chemogenetic approaches reveal dual functions of microglia in epilepsyPreprint
Dheer, A., Bosco, D. B., Zheng, J., Wang, L., Zhao, S., Haruwaka, K., Yi, M., Barath, A. S., Tian, D., & Wu, L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.28.542660
Self-citationGrundlagen der Neuro-/Psychopharmakologie
Gerlach, M., & Drepper, C. (2023) · Springer eBooks · doi:10.1007/978-3-662-65267-1_1
Fröhlich, A., Heuvel, F. O., Rehman, R., Krishnamurthy, S. S., Li, S., Li, Z., Bayer, D., Conquest, A., Hagenston, A. M., Ludolph, A. C., et al. (2022) · DZNE Pub · doi:10.6084/m9.figshare.21601436
Metadata
- Authors
- Umpierre, A. D., & Wu, L.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Wu, Long‐Jun
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2020-12-28
- Volume
- 69
- Issue
- 7
- Pages
- 1637-1653
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC8113084
- OpenAlex
- W3115061260
- Cited by
- 237
- References
- 137
- Citations by year
- 2026: 36 · 2025: 62 · 2024: 52 · 2023: 44 · 2022: 28 · 2021: 14
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS088627, NS110825, NS110949, NS112144, NS114040)
- National Institute on Aging (AG064159)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, microglial motility, microglial morphology, microglial receptors, calcium signaling, neuronal hyperactivity, brain homeostasis, neuroinflammation, circuit modification
- MeSH terms
- Brain, Central Nervous System, Neurons, Microglia, Calcium Signaling
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