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Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice
David M. Feliciano, … , Jean-Claude Platel, Angélique Bordey
David M. Feliciano, … , Jean-Claude Platel, Angélique Bordey
Published March 14, 2011
Citation Information: J Clin Invest. 2011;121(4):1596-1607. https://doi.org/10.1172/JCI44909.
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Technical Advance Neuroscience Article has an altmetric score of 3

Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice

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Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by mutations in Tsc1 or Tsc2 that lead to mammalian target of rapamycin (mTOR) hyperactivity. Patients with TSC suffer from intractable seizures resulting from cortical malformations known as tubers, but research into how these tubers form has been limited because of the lack of an animal model. To address this limitation, we used in utero electroporation to knock out Tsc1 in selected neuronal populations in mice heterozygous for a mutant Tsc1 allele that eliminates the Tsc1 gene product at a precise developmental time point. Knockout of Tsc1 in single cells led to increased mTOR activity and soma size in the affected neurons. The mice exhibited white matter heterotopic nodules and discrete cortical tuber-like lesions containing cytomegalic and multinucleated neurons with abnormal dendritic trees resembling giant cells. Cortical tubers in the mutant mice did not exhibit signs of gliosis. Furthermore, phospho-S6 immunoreactivity was not upregulated in Tsc1-null astrocytes despite a lower seizure threshold. Collectively, these data suggest that a double-hit strategy to eliminate Tsc1 in discrete neuronal populations generates TSC-associated cortical lesions, providing a model to uncover the mechanisms of lesion formation and cortical hyperexcitability. In addition, the absence of glial reactivity argues against a contribution of astrocytes to lesion-associated hyperexcitability.

Authors

David M. Feliciano, Tiffany Su, Jean Lopez, Jean-Claude Platel, Angélique Bordey

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Figure 4

Single-cell Tsc1 deletion at E15 generates tuber-like lesions in Tsc1fl/mut mice.

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Single-cell Tsc1 deletion at E15 generates tuber-like lesions in Tsc1fl/...
(A and B) Photographs of mRFP+ cells in P28 coronal sections from Tsc1fl/WT (A) and Tsc1fl/mut mice (B) electroporated at the onset of layer II/III birth (E15). (C) Diagram of a coronal section illustrating the cortical ROI and the regions of the cortex, consisting of 6, 5, or 3 layers. (D) Bar graphs illustrating the distribution (as a percentage) of mRFP+ cells across cortical layers in Tsc1fl/WT (n = 7) and Tsc1fl/mut mice (n = 4). *P < 0.05; **P < 0.005. (E) Photographs of mRFP+ cells in P28 serial coronal sections (bregma –0.08 to –2.8 mm) from a Tsc1fl/WT mouse electroporated at E15. The black arrows point to scattered white matter cells; white arrow points to a small group of mRFP+ cells. (F) Photograph of mRFP+ cells on a DIC image in the rectangle from the most rostral section in E, illustrating a radial column of migration. (G and H) pS6 immunostaining and corresponding mRFP+ cells in a coronal section from a P28 Tsc1fl/mut mouse. (I) Photograph of mRFP+ cells in the rectangle of the most caudal section in E. Scale bars: 300 μm (A, B, and E), 100 μm (F), 70 μm (G and H), and 140 μm (I). Images are from mice electroporated at E15.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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