Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin
Open accessAbstract
Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that prominently features brain malformations (tubers) with many patients suffering from epilepsy and autism. These malformations typically exhibit neuronal as well as glial cell abnormalities and likely underlie much of the neurological morbidity seen in TSC. Tuber pathogenesis remains poorly understood though upregulation of the mTORC1 signaling pathway in TSC has been consistently demonstrated. Here we address abnormal brain development in TSC by inactivating the mouse Tsc1 gene in embryonic neural progenitor cells. This strategy permits evaluation of the role of the Tsc1 gene in both neuronal as well as glial cell lineages. Tsc1(Emx1-Cre) conditional knockout (CKO) animals die by 25 days of life. Their brains have increased size and contain prominent large cells within the cerebral cortex that have greatly increased mTORC1 signaling and decreased mTORC2 signaling. Severe defects of cortical lamination, enlarged dysmorphic astrocytes and decreased myelination were also found. Tsc1(Emx1-Cre) CKO mice were then treated with rapamycin to see if the premature death and brain abnormalities can be rescued. Postnatal rapamycin treatment completely prevented premature death and largely reversed the glia pathology but not abnormal neuronal lamination. These findings support a model that loss of function of the TSC genes in embryonic neural progenitor cells causes cortical malformations in patients with TSC. The dramatic effect of rapamycin suggests that even with extensive multi-lineage abnormalities, a postnatal therapeutic window may exist for patients with TSC.
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Rapamycin successfully reduced cognitive impairment and social behavior deficit in mouse models of tuberous sclerosis and improved behavior in adult mice with a deletion of PTEN.
“Rapamycin successfully reduced cognitive impairment and social behavior deficit in mouse models of tuberous sclerosis 61-63 and improved behavior in adult mice with a deletion of PTEN 64 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [63]
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- Authors
- Carson, R. P., Van Nielen, D. L., Winzenburger, P. A., & Ess, K. C.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Ess, Kevin C.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 45
- Issue
- 1
- Pages
- 369-380
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC3225598
- OpenAlex
- W2087441158
- Cited by
- 165
- References
- 49
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 4 · 2018: 8 · 2017: 14 · 2016: 15 · 2015: 17 · 2014: 15 · 2013: 20 · 2012: 15
- FWCI
- 10.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (5K08NS050484)
- Vanderbilt Kennedy Center for Research on Human Development
- Tuberous Sclerosis Alliance
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- tuberous sclerosis complex, TSC1, mTORC1 signaling, mTORC2 signaling, rapamycin, cortical lamination, malformations of cortical development, astrocytes, myelination, conditional knockout mice, epilepsy, autism spectrum disorder
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Animals, Brain, Disease Models, Animal, Neuroglia, Neurons, Transcription Factors, Tuberous Sclerosis, Signal Transduction, Cell Death, Mice, Knockout, Sirolimus, Tumor Suppressor Proteins, Mice
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