Tau Loss Attenuates Neuronal Network Hyperexcitability in Mouse and Drosophila Genetic Models of Epilepsy
Open accessAbstract
Neuronal network hyperexcitability underlies the pathogenesis of seizures and is a component of some degenerative neurological disorders such as Alzheimer's disease (AD). Recently, the microtubule-binding protein tau has been implicated in the regulation of network synchronization. Genetic removal of Mapt , the gene encoding tau, in AD models overexpressing amyloid-β (Aβ) decreases hyperexcitability and normalizes the excitation/inhibition imbalance. Whether this effect of tau removal is specific to Aβ mouse models remains to be determined. Here, we examined tau as an excitability modifier in the non-AD nervous system using genetic deletion of tau in mouse and Drosophila models of hyperexcitability. Kcna1 −/− mice lack Kv1.1-delayed rectifier currents and exhibit severe spontaneous seizures, early lethality, and megencephaly. Young Kcna1 −/− mice retained wild-type levels of Aβ, tau, and tau phospho-Thr 231 . Decreasing tau in Kcna1 −/− mice reduced hyperexcitability and alleviated seizure-related comorbidities. Tau reduction decreased Kcna1 −/− video-EEG recorded seizure frequency and duration as well as normalized Kcna1 −/− hippocampal network hyperexcitability in vitro . Additionally, tau reduction increased Kcna1 −/− survival and prevented megencephaly and hippocampal hypertrophy, as determined by MRI. Bang-sensitive Drosophila mutants display paralysis and seizures in response to mechanical stimulation, providing a complementary excitability assay for epistatic interactions. We found that tau reduction significantly decreased seizure sensitivity in two independent bang-sensitive mutant models, kcc and eas . Our results indicate that tau plays a general role in regulating intrinsic neuronal network hyperexcitability independently of Aβ overexpression and suggest that reducing tau function could be a viable target for therapeutic intervention in seizure disorders and antiepileptogenesis.
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Tau ablation confers neuronal protection resulting in the recovery of behavioral deficits in neurodegenerative and neurodevelopmental models.
“Numerous studies across neurodegenerative and neurodevelopmental models have shown that tau ablation confers neuronal protection resulting in the recovery of behavioral deficits [56, 75, 76, 121–123].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [122]
The Results section, “Reducing tau decreases hyperexcitability in bang-sensitive Drosophila mutants” (page unavailable), reports fewer seizure-like behaviors and paralysis after tau reduction; the Discussion also reports reduced seizures in Kcna1−/− mice. But the paper does not establish that neuronal protection caused recovery of behavioral deficits: it says tau loss *may* be neuroprotective and clarifies that its experiments tested absence of tau during development, not reversal of a preexisting disorder. (LLM, conf=0.86)
Experimental — accuracy not yet measuredReducing tau expression can suppress seizures in a mouse model of epilepsy.
“while reducing tau expression can suppress seizures in a mouse model of epilepsy (Holth et al., 2013)”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Holth et al., 2013
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Research works printed but not linked: 36
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- Authors
- Holth, J. K., Bomben, V. C., Reed, J. G., Inoue, T., Younkin, L., Younkin, S. G., Pautler, R. G., Botas, J., & Noebels, J. L.
- Affiliations
- Baylor College of Medicine (US)
- Mayo Clinic (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-01-23
- Volume
- 33
- Issue
- 4
- Pages
- 1651-1659
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3711605
- OpenAlex
- W2114444638
- Cited by
- 238
- References
- 49
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 17 · 2023: 19 · 2022: 16 · 2021: 32 · 2020: 19 · 2019: 19 · 2018: 17 · 2017: 15 · 2016: 12 · 2015: 23 · 2014: 15 · 2013: 9
- FWCI
- 13.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (NIA06656)
- National Institute on Aging (P01AG022074, R01AG006656, R01AG029977)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079638)
- National Institute of Neurological Disorders and Stroke (R01 NS-29709, NS042179, R01NS042179, R56NS042179, R01NS029709)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- tau protein, epilepsy, seizures, KCNA1, Kv1.1, delayed rectifier potassium current, MAPT, amyloid-beta, excitatory-inhibitory imbalance, antiepileptogenesis, tau phosphorylation, Drosophila model, mouse model
- MeSH terms
- Animals, Disease Models, Animal, Drosophila, Electroencephalography, Enzyme-Linked Immunosorbent Assay, Epilepsy, Female, Hippocampus, Male, Mice, Inbred C57BL, Nerve Net, Organ Culture Techniques, Blotting, Western, tau Proteins, Mice, Knockout, Patch-Clamp Techniques, Mice
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