Developmental brain abnormalities in tuberous sclerosis complex: A comparative tissue analysis of cortical tubers and perituberal cortex

Véronique Ruppe, Pelin Dilsiz, Carol Reiss, Chad Carlson, Orrin Devinsky, David Zagzag, Howard L. Weiner, Delia M. Talos

Research output: Contribution to journalArticle

Abstract

Objective Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism. Methods Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell-specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial-specific proteins in tubers and peritubers, as compared to non-TSC epilepsy specimens. Results Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6-positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination. Significance Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal-appearing perituberal cortex. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Original languageEnglish (US)
Pages (from-to)539-550
Number of pages12
JournalEpilepsia
Volume55
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Tuberous Sclerosis
S 6
Brain
Sirolimus
Sclerosis
Giant Cells
Autistic Disorder
Growth
Neurologic Manifestations
Neuroglia
Epilepsy
Biomarkers
Western Blotting
Neurons
mechanistic target of rapamycin complex 1
Proteins
TOR complex 2

Keywords

  • Axons
  • Epileptogenesis
  • Hypomyelination
  • Mammalian target of rapamycin
  • Peri-tuber

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Medicine(all)

Cite this

Developmental brain abnormalities in tuberous sclerosis complex : A comparative tissue analysis of cortical tubers and perituberal cortex. / Ruppe, Véronique; Dilsiz, Pelin; Reiss, Carol; Carlson, Chad; Devinsky, Orrin; Zagzag, David; Weiner, Howard L.; Talos, Delia M.

In: Epilepsia, Vol. 55, No. 4, 2014, p. 539-550.

Research output: Contribution to journalArticle

Ruppe, Véronique ; Dilsiz, Pelin ; Reiss, Carol ; Carlson, Chad ; Devinsky, Orrin ; Zagzag, David ; Weiner, Howard L. ; Talos, Delia M. / Developmental brain abnormalities in tuberous sclerosis complex : A comparative tissue analysis of cortical tubers and perituberal cortex. In: Epilepsia. 2014 ; Vol. 55, No. 4. pp. 539-550.
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AU - Zagzag, David

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AB - Objective Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism. Methods Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell-specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial-specific proteins in tubers and peritubers, as compared to non-TSC epilepsy specimens. Results Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6-positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination. Significance Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal-appearing perituberal cortex. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

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