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TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model

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Shao, Eric, Chang, Che-Wei, Li, Zhiyong, Yu, Xinxing, Ho, Kaitlyn, Zhang, Michelle, Wang, Xin, Simms, Jeffrey +6 more·2022·Science Translational Medicine
DOI 10.1126/scitranslmed.abm5527PMC PMC9102397
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Abstract

Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase–AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.

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  • Selective genetic ablation of tau in hippocampal excitatory neurons but not in inhibitory neurons mediates the neuroprotective effects of tau reduction in the Scn1a model.

    “Shao et al. (2022) further found that selective genetic ablation of tau in hippocampal excitatory neurons but not in inhibitory neurons mediates the neuroprotective effects of tau reduction in the Scn1a model.”

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

    The Results report that tau ablation in excitatory, but not inhibitory, neurons reduced epileptic activity, and the Discussion describes benefits in the Scn1a Dravet syndrome model. However, the Results specify excitatory neurons across multiple forebrain regions, including the hippocampus and neocortex; the study does not isolate hippocampal excitatory neurons as the mediating population. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In multiple mouse disease models, tau ablation is associated with protective effects.

    “Interestingly, in multiple mouse disease models, tau ablation has been associated with protective effects.”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [81]

  • In ASD models, tau knockdown is associated with reduced autistic-like behaviors and decreased seizure susceptibility.

    “In models of ASD, tau knockdown has been associated with reduced autistic-like behaviors and decreased seizure susceptibility [56, 80, 81].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [81]

  • In the Scn1a model, postnatal injection of tau-targeting antisense oligonucleotides also reduces epileptic activity.

    “This effect also occurs in the Scn1a model following postnatal injection of tau-targeting antisense oligonucleotides (Shao et al., 2022), suggesting that antisense oligonucleotides may be a promising treatment avenue for children with Dravet syndrome.”

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

  • 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 Shao et al., 2022

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Authors
Shao, E., Chang, C.-W., Li, Z., Yu, X., Ho, K., Zhang, M., Wang, X., Simms, J., Lo, I., Speckart, J., Holtzman, J., Yu, G.-Q., Roberson, E. D., & Mucke, L.
Affiliations
  • Gladstone Institutes (US)
  • University of Alabama at Birmingham (US)
Corresponding author
  • Shao, Eric
  • Chang, Che-Wei
  • Mucke, Lennart
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-04-27
Volume
14
Issue
642
Pages
eabm5527-eabm5527
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.abm5527
PMC
PMC9102397
OpenAlex
W4225083328
Cited by
54
References
17
Citations by year
2026: 11 · 2025: 17 · 2024: 9 · 2023: 12 · 2022: 5
FWCI
7.01
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute on Aging (P01AG073082)
  • National Institute of Mental Health (R01MH115679)
  • National Institute of Neurological Disorders and Stroke (R01NS075487)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
tau protein, Dravet syndrome, excitatory neurons, antisense oligonucleotides, epilepsy, sudden unexpected death in epilepsy, autism-like behavior, PI3K/AKT/mTOR pathway, megalencephaly, postnatal treatment, mouse model
MeSH terms
Epileptic Syndromes, Sudden Unexpected Death in Epilepsy, Animals, Autistic Disorder, Disease Models, Animal, Epilepsy, Epilepsies, Myoclonic, Humans, Infant, Neurons, Spasms, Infantile, tau Proteins, Phosphatidylinositol 3-Kinases, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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