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Brain. 2015 Feb;138(Pt 2):356-70. doi: 10.1093/brain/awu350. Epub 2014 Dec 16.

Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering.

Author information

1
1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA 2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
2
2 The Centre for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
3
3 Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.
4
1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA.
5
1 Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612, USA 4 Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA.
6
5 Department of Pathology; Wayne State University School of Medicine, Detroit, MI 48201, USA.

Abstract

Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders.

KEYWORDS:

epilepsy genetics; epilepsy surgery; localization-related epilepsy; refractory epilepsy; transcriptomics

PMID:
25516101
PMCID:
PMC4306820
DOI:
10.1093/brain/awu350
[Indexed for MEDLINE]
Free PMC Article

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