Astrocyte‐specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures
Abstract
Persons affected with tuberous sclerosis complex (TSC) develop a wide range of neurological abnormalities including aberrant neuronal migration and seizures. In an effort to model TSC‐associated central nervous system abnormalities in mice, we generated two independent lines of astrocyte‐specific Tsc1 conditional knockout mice by using the Cre‐LoxP system. Astrocyte‐specific Tsc1 ‐null mice exhibit electroencephalographically proven seizures after the first month of age and begin to die at 3 to 4 months. Tsc1 ‐null mice show significant increases in astrocyte numbers throughout the brain by 3 weeks of age and abnormal neuronal organization in the hippocampus between 3 and 5 weeks. Moreover, cultured Tsc1 ‐null astrocytes behave similar to wild‐type astrocytes during log phase growth but demonstrate increased saturation density associated with reduced p27 Kip1 expression. Collectively, our results demonstrate that astrocyte‐specific disruption of Tsc1 in mice provides a context‐dependent growth advantage for astrocytes that results in abnormalities in neuronal organization and epilepsy.
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- Authors
- Uhlmann, E. J., Wong, M., Baldwin, R. L., Bajenaru, M. L., Onda, H., Kwiatkowski, D. J., Yamada, K., & Gutmann, D. H.
- Affiliations
- St. Louis Children's Hospital (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Gutmann, David H.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2002-07-17
- Volume
- 52
- Issue
- 3
- Pages
- 285-296
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2140657162
- Cited by
- 372
- References
- 42
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 13 · 2023: 11 · 2022: 13 · 2021: 16 · 2020: 13 · 2019: 13 · 2018: 11 · 2017: 16 · 2016: 18 · 2015: 20 · 2014: 21 · 2013: 16 · 2012: 38
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ns024279-24, 5r01ns036996-04)
- National Institute of Neurological Disorders and Stroke (NS-31535, NS36996, NS 24279)
- 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, TSC1, astrocytes, conditional knockout mice, seizures, epilepsy, neuronal migration, hippocampus, astrocyte proliferation, p27, astrocyte-neuron interaction
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Animals, Astrocytes, Cell Division, Cells, Cultured, Electroencephalography, Epilepsy, Gliosis, Hippocampus, Neurons, Proteins, Mice, Knockout, Cell Cycle Proteins, Tumor Suppressor Proteins, Cyclin-Dependent Kinase Inhibitor p27, Mice, In Vitro Techniques
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