Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia

M. Cecilia Ljungberg, Meenakshi B. Bhattacharjee, Yaojuan Lu, Dawna L. Armstrong, Daniel Yoshor, John W. Swann, Michael Sheldon, Gabriella D'Arcangelo

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Objective: The cortex of patients with cortical dysplasia contains several abnormal cell types. Among the dysplastic cells, cytomegalic neurons are known to be electrically hyperactive and may contribute to epileptic activity. In this study, we sought to identify molecular markers of cytomegalic neurons in focal or hemispheric cortical dysplasia and to determine whether the activity of the mammalian target of rapamycin (mTOR) kinase is abnormally high in these cells. Methods: Microarray analysis of gene expression in large dysplastic cells microdissected from cortical dysplasia surgical specimens was used to identify markers of cytomegalic neurons. Immunohistochemistry and immunofluorescence analysis of cortical sections was used to validate the microarray results and to probe the activity of mTOR in cytomegalic neurons using phosphospecific antibodies directed against known mTOR targets. Results: We demonstrate that the neurofilament heavy chain is a reliable marker of cytomegalic neurons and that targets of the mTOR kinase, such as the ribosomal protein S6, eIF4G, and Akt, are hyperphosphorylated in these dysplastic neurons. Interpretation: We conclude that mTOR kinase hyperactivation is a molecular mechanism underlying the development of cytomegalic neurons. This finding may lead to the development of novel therapeutic approaches for childhood epilepsy associated with cortical dysplasia.

Original languageEnglish (US)
Pages (from-to)420-429
Number of pages10
JournalAnnals of Neurology
Volume60
Issue number4
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

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    Ljungberg, M. C., Bhattacharjee, M. B., Lu, Y., Armstrong, D. L., Yoshor, D., Swann, J. W., Sheldon, M., & D'Arcangelo, G. (2006). Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Annals of Neurology, 60(4), 420-429. https://doi.org/10.1002/ana.20949