Cited by 48Tuberous Sclerosis Complex ResearchEpilepsy research and treatmentPI3K/AKT/mTOR signaling in cancer

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

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Zimmer, Till S., Broekaart, Diede W. M., Gruber, Victoria-Elisabeth, van Vliet, Erwin A., Mühlebner, Angelika, Aronica, Eleonora·2020·Frontiers in Neurology

Abstract

Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

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  • Reactive astrocytes could drive neuronal hyperexcitability through failure of homeostatic functions, such as glutamate uptake.

    “Reactive astrocytes could drive neuronal hyperexcitability through failure of homeostatic functions, such as glutamate uptake31.”

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Authors
Zimmer, T. S., Broekaart, D. W. M., Gruber, V.-E., van Vliet, E. A., Mühlebner, A., & Aronica, E.
Affiliations
  • Amsterdam Neuroscience (NL)
  • Medical University of Vienna (AT)
Corresponding author
Aronica, Eleonora
Venue
Frontiers in Neurology
Published
2020-09-17
Volume
11
Pages
1028-1028
ISSN
1664-2295 (ISSN-L)
OpenAlex
W3087548944
Cited by
48
References
263
Citations by year
2026: 6 · 2025: 8 · 2024: 11 · 2023: 8 · 2022: 6 · 2021: 9
FWCI
0.73
Type
journal article
Language
en
Open access
Locations
  • Frontiers in Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Stichting TSC Fonds
  • Seventh Framework Programme (602102)
  • H2020 Marie Skłodowska-Curie Actions
  • Epilepsiefonds (16-05)
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
tuberous sclerosis complex, mTOR signaling, epileptogenesis, glial dysfunction, astrocytes, oligodendrocytes, NG2 glia, microglia, mTOR hyperactivation, malformations of cortical development, epilepsy, autism spectrum disorder, intellectual disability, neurodevelopmental disorders

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