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Epilepsy Res. 2017 Jan;129:146-156. doi: 10.1016/j.eplepsyres.2016.12.002. Epub 2016 Dec 7.

FCD Type II and mTOR pathway: Evidence for different mechanisms involved in the pathogenesis of dysmorphic neurons.

Author information

1
Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy. Electronic address: laura.rossini@istituto-besta.it.
2
Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
3
Department of Pediatric Neuroscience, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
4
Epilepsy Surgery Centre "C. Munari", Ospedale Niguarda, Milan, Italy.
5
Neurosurgery Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
6
Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience University of Amsterdam; Stichting Epilepsie Instellingen Nederland (SEIN), The Netherlands.

Abstract

Type II focal cortical dysplasia (FCD II) is a malformation of cortical development, frequently associated with intractable epilepsy, characterised by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). We investigated the expression of pS6 (downstream target) and pPDK1-pAkt (upstream targets) as evidence for mTOR pathway activation and their co-expression with Interleukin-1β in FCD II surgical specimens and compared the findings with control non-epileptic tissue, non-malformed epileptic tissue or acquired epilepsy-Rasmussen's Encephalitis (RE) occasionally presenting pS6 and Interleukin-1β positive abnormal neurons. Downstream mTOR activation was demonstrated in almost all abnormal cells in both FCD II and RE. Conversely, upstream activation in FCD II was observed in the majority of BCs, in a proportion of DNs, not presenting Interleukin-1β expression, but not at all in RE scattered abnormal neurons. Based on these findings we suggest that the presence of BCs and DNs in FCD II could be due to a first upstream mTOR pathway PI3K-Akt-mediate event occurring very early during cortical development in the large proportion of abnormal cells; followed by the appearance of additional pS6 positive DNs promoted by the presence of a later inflammatory processes.

KEYWORDS:

Epilepsy surgery; Focal cortical dysplasia; inflammation; mTOR pathway; pI3K-Akt pathway; pS6

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