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

• Published in: Annals of neurology Vol. 60; no. 4; pp. 420 - 429
• Main Authors: Ljungberg, M. Cecilia, Bhattacharjee, Meenakshi B., Lu, Yaojuan, Armstrong, Dawna L., Yoshor, Daniel, Swann, John W., Sheldon, Michael, D'Arcangelo, Gabriella
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2006; Willey-Liss
• Subjects: Adolescent; Biological and medical sciences; Biomarkers; Biotransformation; Cerebral Cortex - abnormalities; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Child; Dissection; Epilepsy, Temporal Lobe - metabolism; Epilepsy, Temporal Lobe - pathology; Female; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Human viral diseases; Humans; Immunohistochemistry; Infant; Infectious diseases; Isolated neuron and nerve. Neuroglia; Male; Medical sciences; Neurofilament Proteins - biosynthesis; Neurofilament Proteins - genetics; Neurology; Neurons - metabolism; Neurons - pathology; Oligonucleotide Array Sequence Analysis; Protein Kinases - metabolism; Ribosomal Proteins - metabolism; Seizures - etiology; Seizures - pathology; TOR Serine-Threonine Kinases; Translocation, Genetic - genetics; Vertebrates: nervous system and sense organs; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Human; Dysplasia; Nervous system diseases; Neuron; Sirolimus
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.20949

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 phospho‐specific 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. Ann Neurol 2006