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Developmental brain abnormalities in tuberous sclerosis complex: A comparative tissue analysis of cortical tubers and perituberal cortex
Author(s) -
Ruppe Véronique,
Dilsiz Pelin,
Reiss Carol Shoshkes,
Carlson Chad,
Devinsky Orrin,
Zagzag David,
Weiner Howard L.,
Talos Delia M.
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12545
Subject(s) - tuberous sclerosis , tsc1 , tsc2 , mtorc1 , cortex (anatomy) , neuroscience , pi3k/akt/mtor pathway , cortical dysplasia , epileptogenesis , biology , epilepsy , pathology , medicine , signal transduction , microbiology and biotechnology
Summary Objective Genetic loss of T sc1/ T sc2 function in tuberous sclerosis complex ( TSC ) results in altered mammalian target of rapamycin (m TOR) 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 m TORC 1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the m TORC 1 and m TORC 2 biomarkers phospho‐ S 6 ( S er235/236), phospho‐ S 6 ( S er240/244), and phospho‐ A kt ( S er473), 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 p S 6‐positive dysplastic neurons and giant cells, an overall increase in m TORC 1 and a decrease in m TORC 2 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 m TOR 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 .