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Cited by 140Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchAnesthesia and Neurotoxicity Research

Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain

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Venturino, Alessandro, Schulz, Rouven, De Jesús-Cortés, Héctor, Maes, Margaret E., Nagy, Bálint, Reilly-Andújar, Francis, Colombo, Gloria, Cubero, Ryan John A. +3 more·2021·Cell Reports
DOI 10.1016/j.celrep.2021.109313PMC PMC8284881
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Abstract

Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.

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  • Microglia promote and assist various processes within the CNS, closely interacting with neurons, other glial cells, the neurovascular unit and the extracellular matrix.

    “Microglia promote and assist with various processes within the CNS, closely interacting with neurons, other glial cells, the neurovascular unit and the extracellular matrix.”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [23]

    The Results section (“Microglia interact with Pvalb+ neurons and remodel PNN”) documents interactions with neurons, and the Discussion (“Ketamine induces microglia-mediated PNN remodeling”) describes microglial interactions with perineuronal nets, a form of extracellular matrix. Our copy does not establish the claimed close interactions with other glial cells or the neurovascular unit, so it supports only part of the broad statement. Page numbers were not available in the indexed passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Microglia regulate axonal myelination, synaptic pruning, vasculature repair, and clearance of debris and toxic substances.

    “These cells not only regulate axonal myelination, but also contribute to synaptic pruning, vasculature repair, and clearance of debris and toxic substances, among other important physiological roles [23–28].”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [23]

    The Results section reports microglial uptake of perineuronal-net fragments after ketamine exposure, but does not establish the listed roles. Searches of our copy for myelination, synaptic pruning, vasculature repair, and clearance of debris or toxic substances found no passage addressing those claims. No page numbers were available in our copy. (LLM, conf=0.76)

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Research works printed but not linked: 57

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Authors
Venturino, A., Schulz, R., De Jesús-Cortés, H., Maes, M. E., Nagy, B., Reilly-Andújar, F., Colombo, G., Cubero, R. J. A., Schoot Uiterkamp, F. E., Bear, M. F., & Siegert, S.
Affiliations
  • Institute of Science and Technology Austria (AT)
  • Massachusetts Institute of Technology (US)
Corresponding author
Siegert, Sandra
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2021-07
Volume
36
Issue
1
Pages
109313
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2021.109313
PMC
PMC8284881
OpenAlex
W3178213307
Cited by
140
References
87
Citations by year
2026: 15 · 2025: 34 · 2024: 27 · 2023: 23 · 2022: 38 · 2021: 3
FWCI
9.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • Institute of Science and Technology Austria (submittedVersion, cc-by)
Funders
  • European Research Council (715571)
  • Österreichischen Akademie der Wissenschaften
  • Horizon 2020
  • Massachusetts Institute of Technology
  • H2020 Marie Skłodowska-Curie Actions
  • Institute of Science and Technology Austria (665385, 754411)
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 › Anesthesia and Neurotoxicity Research
Keywords
perineuronal nets, microglia, ketamine, parvalbumin interneurons, extracellular matrix, cortical plasticity, critical period plasticity, microglial activation, 40 Hz stimulation, amyloid plaques
MeSH terms
Aging, Anesthetics, Animals, Brain, Female, Ketamine, Light, Mice, Inbred C57BL, Nerve Net, Neuronal Plasticity, Neurons, Parvalbumins, Photic Stimulation, Microglia, Mice

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