A Mouse Model of Tuberous Sclerosis: Neuronal Loss of Tsc1 Causes Dysplastic and Ectopic Neurons, Reduced Myelination, Seizure Activity, and Limited Survival

Tuberous sclerosis (TSC) is a hamartoma syndrome caused by mutations in TSC1 or TSC2 in which cerebral cortical tubers and seizures are major clinical issues. We have engineered mice in which most cortical neurons lose Tsc1 expression during embryonic development. These Tsc1 mutant mice display seve...

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Bibliographic Details
Published in:The Journal of neuroscience 2007-05, Vol.27 (21), p.5546-5558
Main Authors: Meikle, Lynsey, Talos, Delia M, Onda, Hiroaki, Pollizzi, Kristen, Rotenberg, Alexander, Sahin, Mustafa, Jensen, Frances E, Kwiatkowski, David J
Format: Article
Language:English
Subjects:
Animals
Demyelinating Diseases - genetics
Demyelinating Diseases - metabolism
Demyelinating Diseases - pathology
Disease Models, Animal
Female
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Neurons - metabolism
Neurons - pathology
Seizures - genetics
Seizures - metabolism
Seizures - pathology
Survival Rate
Tuberous Sclerosis - genetics
Tuberous Sclerosis - metabolism
Tuberous Sclerosis - mortality
Tuberous Sclerosis - pathology
Tuberous Sclerosis Complex 1 Protein
Tumor Suppressor Proteins - deficiency
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - physiology
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Summary:Tuberous sclerosis (TSC) is a hamartoma syndrome caused by mutations in TSC1 or TSC2 in which cerebral cortical tubers and seizures are major clinical issues. We have engineered mice in which most cortical neurons lose Tsc1 expression during embryonic development. These Tsc1 mutant mice display several neurological abnormalities beginning at postnatal day 5 with subsequent failure to thrive and median survival of 35 d. The mice also display clinical and electrographic seizures both spontaneously and with physical stimulation, and some seizures end in a fatal tonic phase. Many cortical and hippocampal neurons are enlarged and/or dysplastic in the Tsc1 mutant mice, strongly express phospho-S6, and are ectopic in multiple sites in the cortex and hippocampus. There is a striking delay in myelination in the mutant mice, which appears to be caused by an inductive neuronal defect. This new TSC brain model replicates several features of human TSC brain lesions and implicates an important function of Tsc1/Tsc2 in neuronal development.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.5540-06.2007