Neuronal Hyperactivity Recruits Microglial Processes via Neuronal NMDA Receptors and Microglial P2Y12 Receptors after Status Epilepticus
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Microglia are highly dynamic immune cells of the CNS and their dynamism is proposed to be regulated by neuronal activities. However, the mechanisms underlying neuronal regulation of microglial dynamism have not been determined. Here, we found an increased number of microglial primary processes in the hippocampus during KA-induced seizure activity. Consistently, global glutamate induced robust microglial process extension toward neurons in both brain slices and in the intact brain in vivo. The mechanism of the glutamate-induced microglial process extension involves the activation of neuronal NMDA receptors, calcium influx, subsequent ATP release, and microglial response through P2Y12 receptors. Seizure-induced increases in microglial process numbers were also dependent on NMDA receptor activation. Finally, we found that P2Y12 KO mice exhibited reduced seizure-induced increases in microglial process numbers and worsened KA-induced seizure behaviors. Our results elucidate the molecular mechanisms underlying microglia-neuron communication that may be potentially neuroprotective in the epileptic brain.
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Microglial CD39 and P2Y12 deletion leads to increased neuronal hyperexcitability and seizures.
“Altered purinergic signaling through P2Y12 and CD39, where Microglial CD39 and P2Y12 deletion leads to increased neuronal hyperexcitability and seizures [69, 70].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [70]
The section “P2Y12 receptor deficiency worsens acute experimental seizures” reports more severe kainate-induced seizures in P2Y12 knockout mice, supporting the P2Y12-and-seizures part of the claim. Our copy does not report a CD39 deletion experiment or show that either deletion increased neuronal hyperexcitability as a separate outcome. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNeuronal NMDA receptor stimulation can provoke local neuronal ATP release sufficient to induce transient microglial process extension via P2Y12.
“Recent work has suggested that neuronal N-methyl-D-aspartate (NMDA) receptor stimulation can provoke local neuronal ATP release that is sufficient to induce transient microglial process extension via P2Y12 (refs 495049,50).”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [50]
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Microglia: Activity‐dependent regulators of neural circuits
Durán Laforet, V., & Schafer, D. P. (2024) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.15105 · Cited by 32 · see citing works
“70,71 It was further shown that microglia detected neuron-derivedATPgradientslargelythroughthemicroglia-expressed purinergicreceptorP2RY12.”
Background
- Authors
- Eyo, U. B., Peng, J., Swiatkowski, P., Mukherjee, A., Bispo, A., & Wu, L.-J.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-08-06
- Volume
- 34
- Issue
- 32
- Pages
- 10528-10540
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4200107
- OpenAlex
- W2008639289
- Cited by
- 509
- References
- 60
- Citations by year
- 2026: 34 · 2025: 42 · 2024: 69 · 2023: 47 · 2022: 64 · 2021: 62 · 2020: 54 · 2019: 40 · 2018: 26 · 2017: 26 · 2016: 21 · 2015: 22 · 2014: 1
- FWCI
- 12.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM008339)
- National Institute of Neurological Disorders and Stroke (R01NS088627)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- neuronal hyperactivity, status epilepticus, NMDA receptor, P2Y12 receptor, neuron-microglia communication, glutamate, ATP release, calcium influx, kainic acid-induced seizures, hippocampus, epilepsy, neuroprotection
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Hippocampus, Luminescent Proteins, Male, Mice, Transgenic, Neurons, Potassium Chloride, Status Epilepticus, Receptors, N-Methyl-D-Aspartate, Microglia, Excitatory Amino Acid Agents, Receptors, Chemokine, Cell Surface Extensions, Sodium Channel Blockers, Mice, Receptors, Purinergic P2Y12, In Vitro Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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