Hippocampal CA3 transcriptional modules associated with granule cell alterations and cognitive impairment in refractory mesial temporal lobe epilepsy patients

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Silvia Yumi Bando
Fernanda Bernardi Bertonha
Luciana Ramalho Pimentel-Silva
João Gabriel Mansano de Oliveira
Marco Antonio Duarte Carneiro
Mariana Hiromi Manoel Oku
Hung-Tzu Wen
Luiz Henrique Martins Castro
Carlos Alberto Moreira-Filho
机构
[1] Faculdade de Medicina da Universidade de São Paulo,Department of Pediatrics
[2] Faculdade de Ciências Médicas da Universidade Estadual de Campinas,Department of Neurology
[3] UNICAMP,Department of Neurology
[4] Faculdade de Medicina da Universidade de São Paulo,Epilepsy Surgery Group
[5] Hospital das Clínicas da FMUSP,undefined
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In about a third of the patients with epilepsy the seizures are not drug-controlled. The current limitation of the antiepileptic drug therapy derives from an insufficient understanding of epilepsy pathophysiology. In order to overcome this situation, it is necessary to consider epilepsy as a disturbed network of interactions, instead of just looking for changes in single molecular components. Here, we studied CA3 transcriptional signatures and dentate gyrus histopathologic alterations in hippocampal explants surgically obtained from 57 RMTLE patients submitted to corticoamygdalohippocampectomy. By adopting a systems biology approach, integrating clinical, histopathological, and transcriptomic data (weighted gene co-expression network analysis), we were able to identify transcriptional modules highly correlated with age of disease onset, cognitive dysfunctions, and granule cell alterations. The enrichment analysis of transcriptional modules and the functional characterization of the highly connected genes in each trait-correlated module allowed us to unveil the modules’ main biological functions, paving the way for further investigations on their roles in RMTLE pathophysiology. Moreover, we found 15 genes with high gene significance values which have the potential to become novel biomarkers and/or therapeutic targets in RMTLE.
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