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Cited by 138Epilepsy research and treatmentIon channel regulation and functionAlzheimer's disease research and treatments

Tau reduction prevents disease in a mouse model of D ravet syndrome

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Gheyara, Ania L., Ponnusamy, Ravikumar, Djukic, Biljana, Craft, Ryan J., Ho, Kaitlyn, Guo, Weikun, Finucane, Mariel M., Sanchez, Pascal E. +1 more·2014·Annals of Neurology
DOI 10.1002/ana.24230PMC PMC4338764
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Abstract

Objective: Reducing levels of the microtubule‐associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies. Methods: We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage‐gated sodium channel subunit Na v 1.1. We genetically deleted 1 or 2 Tau alleles in mice carrying an Na v 1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, electroencephalographic recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays. Results: Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug‐induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only 1 Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance. Interpretation: Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies. Ann Neurol 2014;76:443–456

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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 [123]

    The Results section (page unavailable) reports that tau ablation prevented memory deficits in Scn1aRX/+ Dravet mice, and the Discussion reports improvements in other behaviors. This supports behavioral improvement in a neurodevelopmental model, but the paper does not establish that neuronal protection caused those improvements; it instead proposes reduced epileptic activity as an explanation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Genetic ablation of tau, even by 50% by inactivation of a single Mapt allele, reduces epileptic activity, high mortality rates, and cognitive deficits in the Scn1a mouse model of Dravet syndrome.

    “Genetic ablation of tau, even by 50% by inactivation of a single Mapt allele, also reduces epileptic activity, high mortality rates, and cognitive deficits in the Scn1a mouse model of Dravet syndrome, a severe and intractable childhood epilepsy that is caused by mutations in the SCN1A gene and can lead to autism (Catterall et al., 2010; Li et al., 2011; Gheyara et al., 2014; Anwar et al., 2019; Ta”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Gheyara et al., 2014

    The Abstract Results and Discussion report that deletion of one Tau allele reduced epileptic activity and improved survival in Scn1aRX/+ mice. The Results section on learning and memory reports improved cognitive performance with tau ablation, but does not establish that deletion of just one allele improved those deficits. The claim extends the 50% reduction finding to cognition without support from our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In genetic mouse models of autism spectrum disorder and Dravet syndrome, tau ablation prevents epilepsy and normalizes mTOR overactivation.

    “In genetic mouse models of ASD and Dravet syndrome, tau ablation prevents epilepsy and normalizes mTOR overactivation (Gheyara et al., 2014; Tai et al., 2020; Shao et al., 2022), suggesting that reducing tau may be beneficial in these diseases via PTEN disinhibition.”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Gheyara et al., 2014

    The Abstract Results report that tau ablation reduced spontaneous and febrile seizures in Dravet mice; the Results also report that it prevented heat-induced seizures in a small group. The paper does not establish that epilepsy was prevented altogether, and our copy does not report normalization of mTOR overactivation. The ASD-model and PTEN claims are not assigned specifically to Gheyara et al. among the sentence’s multiple citations. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Neuroprotective effects of tau ablation against not only seizures but also cognitive deficits in animal models of autism spectrum disorder and Dravet syndrome provide evidence for a role of tau in mediating cognitive impairment in these diseases.

    “Furthermore, the neuroprotective effects of tau ablation against not only seizures but also cognitive deficits in animal models of ASD and Dravet syndrome (Gheyara et al., 2014; Tai et al., 2020) provide evidence for a role of tau in mediating cognitive impairment in these diseases as well.”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Gheyara et al., 2014

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References 89 · Cited by 138

Research works printed but not linked: 77

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Authors
Gheyara, A. L., Ponnusamy, R., Djukic, B., Craft, R. J., Ho, K., Guo, W., Finucane, M. M., Sanchez, P. E., & Mucke, L.
Affiliations
University of California, San Francisco (US)
Corresponding author
Mucke, Lennart
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2014-08-13
Volume
76
Issue
3
Pages
443-456
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.24230
PMC
PMC4338764
OpenAlex
W1546797865
Cited by
138
References
89
Citations by year
2026: 11 · 2025: 4 · 2024: 10 · 2023: 8 · 2022: 11 · 2021: 16 · 2020: 19 · 2019: 15 · 2018: 12 · 2017: 11 · 2016: 6 · 2015: 14 · 2014: 1
FWCI
8.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Neurology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NS066930, NS041787)
  • S. D. Bechtel, Jr. Foundation and Stephen Bechtel Fund
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Dravet syndrome, tau protein, SCN1A, Nav1.1 sodium channel, genetic epilepsy, drug-resistant epilepsy, febrile seizures, learning and memory impairment, nest building behavior, mouse model
MeSH terms
Alleles, Animals, Behavior, Animal, Disease Models, Animal, Electroencephalography, Epilepsies, Myoclonic, Female, Hippocampus, Learning, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mutation, Seizures, tau Proteins, Mice, Knockout, Mice, NAV1.1 Voltage-Gated Sodium Channel

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