Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy
Open accessAbstract
Microglia are well known to play a critical role in maintaining brain homeostasis. However, their role in epileptogenesis has yet to be determined. Here, we demonstrate that elevated mTOR signaling in mouse microglia leads to phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without a significant induction of pro-inflammatory cytokines. We further provide evidence that these noninflammatory changes in microglia disrupt homeostasis of the CNS, leading to reduced synapse density, marked microglial infiltration into hippocampal pyramidal layers, moderate neuronal degeneration, and massive proliferation of astrocytes. Moreover, the mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, we have revealed an epileptogenic mechanism that is independent of the microglial inflammatory response. Our data suggest that microglia could be an opportune target for epilepsy prevention.
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Loss and deficiency of the CX3CR1 receptor can alter microglial number, subsequently altering microglia-mediated synaptic pruning during developmental ages.
“Its loss and deficiency can alter microglial number, subsequently altering microglia-mediated synaptic pruning during developmental ages13,18.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [18]
The Results report reduced Cx3cr1 expression and increased microglial numbers in TSC1Cx3cr1CKO mice. The Discussion suggests that increased microglial numbers and phagocytosis could account for reduced synapse density, but it does not establish that CX3CR1 loss caused either change; it attributes the proliferation to elevated mTOR signaling following TSC1 deletion. The proposed effect on pruning is therefore only partly supported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe CX3CR1 receptor is involved in neuron-microglia fractalkine signaling, which plays a vital role in microglial developmental synaptic pruning and homeostasis.
“The CX3CR1 receptor is involved in neuron-microglia fractalkine signaling, which plays a vital role in microglial developmental synaptic pruning and homeostasis.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [18]
The Results section on inflammatory responses reports high CX3CR1 expression in microglia. The Introduction and Discussion describe microglial roles in developmental synaptic pruning and CNS homeostasis, but do not connect those roles to CX3CR1 or describe neuron–microglia fractalkine signaling (pages unavailable in our copy). (LLM, conf=0.86)
Experimental — accuracy not yet measuredAmong the three fluorescent reporters tested, the mT/mG reporter line appears to consistently deliver GFP reporter expression in a cre-dependent manner.
“Among the three fluorescent reporters tested, the mT/mG reporter line appears to consistently deliver GFP reporter expression in a cre-dependent manner, not only in the present study, but also in many other studies (Zhao et al., 2018).”
From Targeting Microglia Using Cx3cr1-Cre Lines: Revisiting the Specificity (2019) · cites this paper as Zhao et al., 2018
The Experimental Procedures (Animals; page unavailable) identify the Rosa mT/mG line among the mice used, so Zhao et al. is an example of a study using that line. Our copy does not report whether the line consistently produced Cre-dependent GFP expression or compare it with other fluorescent reporters. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThis potential embryonic deletion of TSC1 may explain the differences in seizure susceptibility observed in these two studies (Jung et al., 2000; Zhang et al., 2018; Zhao et al., 2018).
“which may explain the differences in seizure susceptibility observed in these two studies (Jung et al., 2000; Zhang et al., 2018; Zhao et al., 2018).”
From Targeting Microglia Using Cx3cr1-Cre Lines: Revisiting the Specificity (2019) · cites this paper as Zhao et al., 2018
The Results section (page unavailable) reports seizures after TSC1 deletion in microglia and acknowledges that deletion during brain development could contribute to epilepsy. It also reports seizures after deletion in adult mice. The paper does not attribute differences in seizure susceptibility between the two cited studies to potential embryonic deletion. (LLM, conf=0.80)
Experimental — accuracy not yet measuredIn Zhao et al. (2018), the Cx3cr1-CreERT2 line developed by Jung et al. (2000) was employed to deplete TSC1 in microglia.
“In the study by Zhao et al. (2018), this line was employed to deplete TSC1 in microglia.”
From Targeting Microglia Using Cx3cr1-Cre Lines: Revisiting the Specificity (2019) · cites this paper as Zhao et al. (2018)
The Results section (‘Elevated mTOR Signaling in Microglia Is Sufficient to Promote the Development of SRSs’; page unavailable) confirms that Zhao et al. crossed a Cx3cr1-CreERT2 line with TSC1-floxed mice to delete TSC1 in microglia. It identifies the Cx3cr1-CreERT2 line with Parkhurst et al. (2013), not Jung et al. (2000), so the claim's identification of the line is unsupported. (LLM, conf=0.90)
Experimental — accuracy not yet measured
On tamoxifen treatment, a fraction of mice in Zhao et al. (2018) displayed spontaneous seizures.
“On tamoxifen treatment, a fraction of mice displayed spontaneous seizures.”
From Targeting Microglia Using Cx3cr1-Cre Lines: Revisiting the Specificity (2019) · cites this paper as Zhao et al. (2018)
Exacerbated activation of microglia promotes microglia-mediated neuronal attrition.
“Exacerbated activation of microglia has been shown to promote microglia-mediated neuronal attrition7,8.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [8]
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- Authors
- Zhao, X., Liao, Y., Morgan, S., Mathur, R., Feustel, P., Mazurkiewicz, J., Qian, J., Chang, J., Mathern, G. W., Adamo, M. A., Ritaccio, A. L., Gruenthal, M., Zhu, X., & Huang, Y.
- Affiliations
- Albany Medical College (US)
- University of California, Los Angeles (US)
- Corresponding author
- Huang, Yunfei
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 22
- Issue
- 8
- Pages
- 2080-2093
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5880308
- OpenAlex
- W2788589260
- Cited by
- 190
- References
- 34
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 20 · 2023: 12 · 2022: 21 · 2021: 36 · 2020: 28 · 2019: 25 · 2018: 9
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (NS093045, DK099566, DK088950)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, epileptogenesis, mTOR signaling, microglial proliferation, phagocytosis, synaptic density, hippocampus, neurodegeneration, astrocyte proliferation, spontaneous recurrent seizures, epilepsy prevention, brain homeostasis
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Animals, Astrocytes, Brain, Epilepsy, Female, Inflammation, Lysosomes, Male, Mice, Inbred C57BL, Phagocytosis, Recurrence, Synapses, Signal Transduction, Gene Deletion, Microglia, Mice, Knockout, Inflammation Mediators, Chemokines, Cell Proliferation, TOR Serine-Threonine Kinases
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