Microglial Morphology and Dynamic Behavior Is Regulated by Ionotropic Glutamatergic and GABAergic Neurotransmission
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PURPOSE: Microglia represent the primary resident immune cells in the CNS, and have been implicated in the pathology of neurodegenerative diseases. Under basal or "resting" conditions, microglia possess ramified morphologies and exhibit dynamic surveying movements in their processes. Despite the prominence of this phenomenon, the function and regulation of microglial morphology and dynamic behavior are incompletely understood. We investigate here whether and how neurotransmission regulates "resting" microglial morphology and behavior. METHODS: We employed an ex vivo mouse retinal explant system in which endogenous neurotransmission and dynamic microglial behavior are present. We utilized live-cell time-lapse confocal imaging to study the morphology and behavior of GFP-labeled retinal microglia in response to neurotransmitter agonists and antagonists. Patch clamp electrophysiology and immunohistochemical localization of glutamate receptors were also used to investigate direct-versus-indirect effects of neurotransmission by microglia. RESULTS: Retinal microglial morphology and dynamic behavior were not cell-autonomously regulated but are instead modulated by endogenous neurotransmission. Morphological parameters and process motility were differentially regulated by different modes of neurotransmission and were increased by ionotropic glutamatergic neurotransmission and decreased by ionotropic GABAergic neurotransmission. These neurotransmitter influences on retinal microglia were however unlikely to be directly mediated; local applications of neurotransmitters were unable to elicit electrical responses on microglia patch-clamp recordings and ionotropic glutamatergic receptors were not located on microglial cell bodies or processes by immunofluorescent labeling. Instead, these influences were mediated indirectly via extracellular ATP, released in response to glutamatergic neurotransmission through probenecid-sensitive pannexin hemichannels. CONCLUSIONS: Our results demonstrate that neurotransmission plays an endogenous role in regulating the morphology and behavior of "resting" microglia in the retina. These findings illustrate a mode of constitutive signaling between the neural and immune compartments of the CNS through which immune cells may be regulated in concert with levels of neural activity.
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Microglia have the capacity to interact with synaptic elements in response to neurotransmitter release and/or sensory experience.
“Previous work has demonstrated that microglia have the capacity to interact with synaptic elements in response to neurotransmitter release and/or sensory experience (Biber et al., 2007; Fontainhas et al., 2011; Nimmerjahn et al., 2005; Ransohoff and Perry, 2009; Tremblay et al., 2010a; Wake et al., 2009).”
From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Fontainhas et al., 2011
The Introduction reports that microglial processes repeatedly contact nearby neurons, and the Discussion says neurotransmission rapidly regulates microglial morphology and behavior in retinal explants. The paper does not demonstrate that neurotransmitter release causes microglia to interact specifically with synaptic elements; it discusses synaptic pruning as a finding suggested by earlier studies. It does not test sensory experience. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMicroglia respond to changes in ionotropic neurotransmission via the intermediary release of ATP by astrocytes.
“and that microglia respond to changes in ionotropic neurotransmission via the intermediary release of ATP by astrocytes20.”
From Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex (2016) · cites this paper as [20]
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- Authors
- Fontainhas, A. M., Wang, M., Liang, K. J., Chen, S., Mettu, P., Damani, M., Fariss, R. N., Li, W., & Wong, W. T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Wong, Wai T.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-01-25
- Volume
- 6
- Issue
- 1
- Pages
- e15973
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3026789
- OpenAlex
- W1997602206
- Cited by
- 334
- References
- 57
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 15 · 2023: 18 · 2022: 20 · 2021: 44 · 2020: 30 · 2019: 28 · 2018: 19 · 2017: 27 · 2016: 28 · 2015: 21 · 2014: 20 · 2013: 24 · 2012: 12
- FWCI
- 11.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Eye Institute
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- microglia, microglial morphology, microglial motility, resting microglia, retinal microglia, extracellular ATP, glutamate receptors, neuroimmune signaling, neurodegenerative diseases
- MeSH terms
- Animals, Immune System, Synaptic Transmission, Retina, Microglia, Receptors, GABA, Microscopy, Video, Cell Shape, Green Fluorescent Proteins, Mice, Receptors, Ionotropic Glutamate, In Vitro Techniques
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