Activation of Neuronal NMDA Receptors Triggers Transient ATP-Mediated Microglial Process Outgrowth
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Microglia are morphologically dynamic cells that rapidly extend their processes in response to various stimuli including extracellular ATP. In this study, we tested the hypothesis that stimulation of neuronal NMDARs trigger ATP release leading to communication with microglia. We used acute mouse hippocampal brain slices and two-photon laser scanning microscopy to study microglial dynamics and developed a novel protocol for fixation and immunolabeling of microglia processes. Similar to direct topical ATP application in vivo, short multiple applications of NMDA triggered transient microglia process outgrowth that was reversible and repeatable indicating that this was not due to excitotoxic damage. Stimulation of NMDAR was required as NMDAR antagonists, but not blockers of AMPA/kainate receptors or voltage-gated sodium channels, prevented microglial outgrowth. We report that ATP release, secondary to NMDAR activation, was the key mediator of this neuron-microglia communication as both blocking purinergic receptors and inhibiting hydrolysis of ATP to prevent locally generated gradients abolished outgrowth. Pharmacological and genetic analyses showed that the NMDA-triggered microglia process extension was independent of Pannexin 1, the ATP releasing channels, ATP release from astrocytes via connexins, and nitric oxide generation. Finally, using whole-cell patch clamping we demonstrate that activation of dendritic NMDAR on single neurons is sufficient to trigger microglia process outgrowth. Our results suggest that dendritic neuronal NMDAR activation triggers ATP release via a Pannexin 1-independent manner that induces outgrowth of microglia processes. This represents a novel uncharacterized form of neuron-microglial communication mediated by ATP.
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Neuronal 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 [49]
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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
- Dissing-Olesen, L., LeDue, J. M., Rungta, R. L., Hefendehl, J. K., Choi, H. B., & MacVicar, B. A.
- Affiliations
- University of British Columbia (CA)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-08-06
- Volume
- 34
- Issue
- 32
- Pages
- 10511-10527
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6802598
- OpenAlex
- W2028167589
- Cited by
- 286
- References
- 68
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 38 · 2023: 21 · 2022: 30 · 2021: 34 · 2020: 31 · 2019: 31 · 2018: 24 · 2017: 21 · 2016: 19 · 2015: 12 · 2014: 1
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Fondation Leducq
- Canadian Institutes of Health Research (10677, 10677 TCE-117869)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- NMDA receptor, neuron-microglia communication, extracellular ATP release, purinergic signaling, pannexin 1, hippocampus, nitric oxide
- MeSH terms
- Adenosine Triphosphate, Animals, Brain, Calcium-Binding Proteins, Female, Magnesium, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Neurons, Time Factors, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Microglia, Patch-Clamp Techniques, Excitatory Amino Acid Agents, Cell Growth Processes, Mice, Receptors, Purinergic P2Y12, In Vitro Techniques
About these checks
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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