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

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Meikle, Lynsey, Talos, Delia M., Onda, Hiroaki, Pollizzi, Kristen, Rotenberg, Alexander, Sahin, Mustafa, Jensen, Frances E., Kwiatkowski, David J.·2007·The Journal of Neuroscience
DOI 10.1523/jneurosci.5540-06.2007PMC PMC6672762
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Abstract

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.

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Figures

Figure 1 Tsc1 c -SynICre + survival, weight gain, phenotype, and EEG. A , Cumulative survival curve for Tsc1 c -SynICre + (filled squares) and control (open squares) mice. B , Weight gain of Tsc1 c -SynICre + (filled squares) and control (open squares) mice. C , Photograph of P21 Tsc1 c -SynICre + mousedemonstrateshunchedback,Straubtail, and out-turned paws. D , EEG segments (10 s) showingnormalcontinuouscontrolmousebackground(I),aspikeburstoccurringinasomewhatirregularbackgroundinamutant mouse (II), relative high-frequency desynchronization during a tonic seizure in a Tsc1 c -SynICre + mouse (III), and frequent high-amplitude sharp waves in a mutant mouse (IV).
Figure 1 Tsc1 c -SynICre + survival, weight gain, phenotype, and EEG. A , Cumulative survival curve for Tsc1 c -SynICre + (filled squares) and control (open squares) mice. B , Weight gain of Tsc1 c -SynICre + (filled squares) and control (open squares) mice. C , Photograph of P21 Tsc1 c -SynICre + mousedemonstrateshunchedback,Straubtail, and out-turned paws. D , EEG segments (10 s) showingnormalcontinuouscontrolmousebackground(I),aspikeburstoccurringinasomewhatirregularbackgroundinamutant mouse (II), relative high-frequency desynchronization during a tonic seizure in a Tsc1 c -SynICre + mouse (III), and frequent high-amplitude sharp waves in a mutant mouse (IV).CC-BY-NC-SA · From the PDF
Figure 2 Loss of Tsc1 and brain structural abnormalities in the Tsc1 c -SynICre + mice . A , Southern blot analysis demonstrating recombination in brain DNA samples from Tsc1 c -SynICre + compared with Tsc1 c -SynICre -mice. The 4.2 kb ( c allele) and 2.4 kb ( -allele) bands are of equal intensity in the Tsc1 c -SynICre -samples, whereas there is a marked shift from the 4.2 kb to the 2.4 kb band in the Tsc1 c -SynICre + samples from cortex (Cor) and diencephalon (Dien) but not cerebellum (Cere). B , Immunoblot analysis showing reduction in expression of both tuberin (Tsc2) and hamartin (Tsc1), and elevated pS6 (S240 -244) in the brains of Tsc1 c -SynICre + mice. AKT is a loading control. NeuN and NSE blots show no difference between Tsc1 c -SynICre + and control mice. C , D , Coronal sections from P21 Tsc1 cw SynICre + ( C ) and Tsc1 c -SynICre + ( D ) mice stained with H&E demonstrate an additional layer of cells at the base of the mutant cortex (asterisk) and widespread cell enlargement ( Ca , Da ). Cb , Cc , Db , Dc , Higher magnification of cortex layer V ( Cb , Db ) and layer VI ( Cc , Dc ) shows enlarged cells in both of these regions of Tsc1 c -SynICre + brain. E , F , Combined X-gal-pS6 immunoperoxidase staining of coronal sections reveals widespread recombination in the form of X-gal product, which is blue in both Tsc1 cw SynICre + ( E ) and Tsc1 c -SynICre + mice ( F ). Ea , Fa , In contrast to control ( Ea ), in the Tsc1 c -SynICre + brain ( Fa ), enlarged pS6 + cells (brown) in layer V, base of cortex (asterisk), and the stratum oriens (arrowheads) of the hippocampal CA1, associate with the X-gal blue precipitate. Eb , Fb , High-power view of stratum oriens shows a correlation between blue stain indicating cre expression, pS6 positivity, and cell enlargement in Tsc1 c -SynICre + mice. Scale bars: Ca , Da , 50 𝛍 m; Cb , Cc , Db , Dc , 25 𝛍 m; Ea , Fa , 20 𝛍 m; Eb , Fb , 25 𝛍 m.
Figure 2 Loss of Tsc1 and brain structural abnormalities in the Tsc1 c -SynICre + mice . A , Southern blot analysis demonstrating recombination in brain DNA samples from Tsc1 c -SynICre + compared with Tsc1 c -SynICre -mice. The 4.2 kb ( c allele) and 2.4 kb ( -allele) bands are of equal intensity in the Tsc1 c -SynICre -samples, whereas there is a marked shift from the 4.2 kb to the 2.4 kb band in the Tsc1 c -SynICre + samples from cortex (Cor) and diencephalon (Dien) but not cerebellum (Cere). B , Immunoblot analysis showing reduction in expression of both tuberin (Tsc2) and hamartin (Tsc1), and elevated pS6 (S240 -244) in the brains of Tsc1 c -SynICre + mice. AKT is a loading control. NeuN and NSE blots show no difference between Tsc1 c -SynICre + and control mice. C , D , Coronal sections from P21 Tsc1 cw SynICre + ( C ) and Tsc1 c -SynICre + ( D ) mice stained with H&E demonstrate an additional layer of cells at the base of the mutant cortex (asterisk) and widespread cell enlargement ( Ca , Da ). Cb , Cc , Db , Dc , Higher magnification of cortex layer V ( Cb , Db ) and layer VI ( Cc , Dc ) shows enlarged cells in both of these regions of Tsc1 c -SynICre + brain. E , F , Combined X-gal-pS6 immunoperoxidase staining of coronal sections reveals widespread recombination in the form of X-gal product, which is blue in both Tsc1 cw SynICre + ( E ) and Tsc1 c -SynICre + mice ( F ). Ea , Fa , In contrast to control ( Ea ), in the Tsc1 c -SynICre + brain ( Fa ), enlarged pS6 + cells (brown) in layer V, base of cortex (asterisk), and the stratum oriens (arrowheads) of the hippocampal CA1, associate with the X-gal blue precipitate. Eb , Fb , High-power view of stratum oriens shows a correlation between blue stain indicating cre expression, pS6 positivity, and cell enlargement in Tsc1 c -SynICre + mice. Scale bars: Ca , Da , 50 𝛍 m; Cb , Cc , Db , Dc , 25 𝛍 m; Ea , Fa , 20 𝛍 m; Eb , Fb , 25 𝛍 m.CC-BY-NC-SA · From the PDF
Figure 3 Increased pS6 and widespread architectural abnormalities in P21 Tsc1 c -SynICre + mice. A-F , In the RSG region of the motor cortex, there is increased pS6 expression in multiple cell layers, including a layer of pS6 + neurons at the base of the cortex in Tsc1 c -SynICre + mice ( D-F ). G-L , In the somatosensory cortex, pS6 + neurons are prominent in cortical layer V and at the gray-white matter border at the base of the cortex in Tsc1 c -SynICre + mice ( J-L ). Occasional large pS6 + neurons are seen in the CA1 pyramidal cell layer of the hippocampus but are also seen ectopically in the stratum oriens. M-R , In the hippocampal CA3 region, nearly all neurons are pS6 + , including those outside the pyramidal cell layer in Tsc1 c -SynICre + mice ( P-R ). S-X , In the dentate gyrus, there are occasional enlarged pS6 + cells in the granule cell layer in Tsc1 c -SynICre + ( V-X ) mice. However, cells within the hilus are more severely affected, and ectopic pS6 + neurons are also apparent. Scale bars: A-F , 85 𝛍 m; G-X , 50 𝛍 m.
Figure 3 Increased pS6 and widespread architectural abnormalities in P21 Tsc1 c -SynICre + mice. A-F , In the RSG region of the motor cortex, there is increased pS6 expression in multiple cell layers, including a layer of pS6 + neurons at the base of the cortex in Tsc1 c -SynICre + mice ( D-F ). G-L , In the somatosensory cortex, pS6 + neurons are prominent in cortical layer V and at the gray-white matter border at the base of the cortex in Tsc1 c -SynICre + mice ( J-L ). Occasional large pS6 + neurons are seen in the CA1 pyramidal cell layer of the hippocampus but are also seen ectopically in the stratum oriens. M-R , In the hippocampal CA3 region, nearly all neurons are pS6 + , including those outside the pyramidal cell layer in Tsc1 c -SynICre + mice ( P-R ). S-X , In the dentate gyrus, there are occasional enlarged pS6 + cells in the granule cell layer in Tsc1 c -SynICre + ( V-X ) mice. However, cells within the hilus are more severely affected, and ectopic pS6 + neurons are also apparent. Scale bars: A-F , 85 𝛍 m; G-X , 50 𝛍 m.CC-BY-NC-SA · From the PDF
Figure 4 Tsc1 c -SynICre + interneurons are pS6 + and enlarged. A-F , Confocal images demonstrate that GAD67 + interneurons in P21 Tsc1 c -SynICre + mice ( D-F ) are enlarged and pS6 + compared with control brain interneurons ( A-C ). Insets, Size comparison for single cells (arrowheads). In addition, some ectopic neurons in the white matter of Tsc1 c -SynICre + brains are pS6 + GAD67 + interneurons (*). Scale bars, 20 𝛍 m.
Figure 4 Tsc1 c -SynICre + interneurons are pS6 + and enlarged. A-F , Confocal images demonstrate that GAD67 + interneurons in P21 Tsc1 c -SynICre + mice ( D-F ) are enlarged and pS6 + compared with control brain interneurons ( A-C ). Insets, Size comparison for single cells (arrowheads). In addition, some ectopic neurons in the white matter of Tsc1 c -SynICre + brains are pS6 + GAD67 + interneurons (*). Scale bars, 20 𝛍 m.CC-BY-NC-SA · From the PDF
Figure 5 mTORC1 activation resulting from Tsc1 loss is restricted to neurons in Tsc1 c -SynICre + mice. A-F , GFAP-positive astrocytes in the CA3 region of the hippocampus are distinct from pS6 + neurons in both P21 control ( A-C ) and Tsc1 c -SynICre + ( D-F ) brains. D-I , The number and distribution of GFAP-positive cells in the Tsc1 c -SynICre + hippocampus ( D-F ) and cortex ( G-I ) shows no evidence for astrogliosis in the mutant brain. Scale bars: A-F , 20 𝛍 m; G-I , 50 𝛍 m.
Figure 5 mTORC1 activation resulting from Tsc1 loss is restricted to neurons in Tsc1 c -SynICre + mice. A-F , GFAP-positive astrocytes in the CA3 region of the hippocampus are distinct from pS6 + neurons in both P21 control ( A-C ) and Tsc1 c -SynICre + ( D-F ) brains. D-I , The number and distribution of GFAP-positive cells in the Tsc1 c -SynICre + hippocampus ( D-F ) and cortex ( G-I ) shows no evidence for astrogliosis in the mutant brain. Scale bars: A-F , 20 𝛍 m; G-I , 50 𝛍 m.CC-BY-NC-SA · From the PDF
Figure 6 Enlarged, dysplastic pyramidal neurons in Tsc1 c -SynICre + brains. A-C , E-G , In the RSG region of the motor cortex, the majority of pyramidal neurons identified by SMI 311 staining in layers V and III are strongly pS6 + in P21 Tsc1 c -SynICre + ( E-G ) mice, in contrast to controls ( A-C ). E-G , Disruption of normal cortical lamination in Tsc1 c -SynICre + mice is also evident, with enlarged SMI 311 + /pS6 + cells outside layers III and V. H , Confocal images of layer V pyramidal neurons show enlarged dysplastic neurons with thickened dendritic arbors in Tsc1 c -SynICre + mice (compare with D ). I , J , Higher-power view of typical enlarged dysplastic SMI 311 + /pS6 + neurons in cortical layer V ( I ) and in the granule cell layer of the dentate gyrus ( J ) in Tsc1 c -SynICre + mice. K , Quantitative size analysis of SMI 311 + cells ( y -axis, pixels) in layer V ( -2 to -2.2 mm from bregma and 3.2-3.4 mm lateral to midline) shows increased soma size in Tsc1 c -SynICre + mice when compared with controls ( p = 0.0002). Scale bars: A-C , E-G , 100 𝛍 m; D , H , 25 𝛍 m; I , J , 10 𝛍 m.
Figure 6 Enlarged, dysplastic pyramidal neurons in Tsc1 c -SynICre + brains. A-C , E-G , In the RSG region of the motor cortex, the majority of pyramidal neurons identified by SMI 311 staining in layers V and III are strongly pS6 + in P21 Tsc1 c -SynICre + ( E-G ) mice, in contrast to controls ( A-C ). E-G , Disruption of normal cortical lamination in Tsc1 c -SynICre + mice is also evident, with enlarged SMI 311 + /pS6 + cells outside layers III and V. H , Confocal images of layer V pyramidal neurons show enlarged dysplastic neurons with thickened dendritic arbors in Tsc1 c -SynICre + mice (compare with D ). I , J , Higher-power view of typical enlarged dysplastic SMI 311 + /pS6 + neurons in cortical layer V ( I ) and in the granule cell layer of the dentate gyrus ( J ) in Tsc1 c -SynICre + mice. K , Quantitative size analysis of SMI 311 + cells ( y -axis, pixels) in layer V ( -2 to -2.2 mm from bregma and 3.2-3.4 mm lateral to midline) shows increased soma size in Tsc1 c -SynICre + mice when compared with controls ( p = 0.0002). Scale bars: A-C , E-G , 100 𝛍 m; D , H , 25 𝛍 m; I , J , 10 𝛍 m.CC-BY-NC-SA · From the PDF
Figure 7 Hypomyelination in Tsc1 c -SynICre + brains. A-F , Compared with controls ( A-C ), the RSG region of motor cortex of Tsc1 c -SynICre + brains shows a marked reduction in MBP expression ( D-F ) in the corpus callosum, the pericallosal white matter, and radiating fibers extending into the cerebral cortex. Scale bars, 100 𝛍 m.
Figure 7 Hypomyelination in Tsc1 c -SynICre + brains. A-F , Compared with controls ( A-C ), the RSG region of motor cortex of Tsc1 c -SynICre + brains shows a marked reduction in MBP expression ( D-F ) in the corpus callosum, the pericallosal white matter, and radiating fibers extending into the cerebral cortex. Scale bars, 100 𝛍 m.CC-BY-NC-SA · From the PDF
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Metadata

Authors
Meikle, L., Talos, D. M., Onda, H., Pollizzi, K., Rotenberg, A., Sahin, M., Jensen, F. E., & Kwiatkowski, D. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Boston Children's Hospital (US)
Corresponding author
Jensen, Frances E.
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2007-05-23
Volume
27
Issue
21
Pages
5546-5558
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.5540-06.2007
PMC
PMC6672762
OpenAlex
W2024191529
Cited by
462
References
68
Citations by year
2026: 9 · 2025: 17 · 2024: 14 · 2023: 14 · 2022: 20 · 2021: 27 · 2020: 23 · 2019: 22 · 2018: 29 · 2017: 23 · 2016: 25 · 2015: 37 · 2014: 31 · 2013: 35 · 2012: 50
FWCI
12.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Tuberous Sclerosis Alliance
  • National Institutes of Health (DP1OD003347, NS31718, NS24279)
  • National Institute of Neurological Disorders and Stroke (NS31718, R01NS031718, R56NS031718, P01NS024279, NS 24279)
Topics
  • Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
Keywords
tuberous sclerosis complex, TSC1, TSC2, mouse model, cortical tubers, neuronal loss, ectopic neurons, seizures, hippocampus, phospho-S6, neuronal development, survival
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Animals, Demyelinating Diseases, Disease Models, Animal, Female, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Seizures, Tuberous Sclerosis, Survival Rate, Tumor Suppressor Proteins, Mice

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