title: Developmental brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of cortical tubers and perituberal cortex.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurology, School of Medicine, New York University, New York, New York, U.S.A.
authors: Véronique
authors: V
authors: Ruppe
authors: Pelin
authors: P
authors: Dilsiz
authors: Carol Shoshkes
authors: CS
authors: Reiss
authors: Chad
authors: C
authors: Carlson
authors: Orrin
authors: O
authors: Devinsky
authors: David
authors: D
authors: Zagzag
authors: Howard L
authors: HL
authors: Weiner
authors: Delia M
authors: DM
authors: Talos
mesh_terms: D001921:Brain / Q000002:abnormalities* / Q000254:growth & development; D001927:Brain Diseases / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000002:abnormalities / Q000254:growth & development / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D014402:Tuberous Sclerosis / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology
keywords: Axons; Epileptogenesis; Hypomyelination; Mammalian target of rapamycin; Peri-tuber