Community Structure Analysis of Transcriptional Networks Reveals Distinct Molecular Pathways for Early- and Late-Onset Temporal Lobe Epilepsy with Childhood Febrile Seizures

Author(s)

Moreira-Filho, Carlos Alberto ^[1] ; Bando, Silvia Yumi ^[1] ; Bertonha, Fernanda Bernardi ^[1] ; Iamashita, Priscila ^[1] ; Silva, Filipi Nascimento ^[2] ; Costa, Luciano da Fontoura ^[2] ; Silva, Alexandre Valotta ^[3] ; Martins Castro, Luiz Henrique ^{[4, 5]} ; Wen, Hung-Tzu ^[6]

Affiliation

^[1] FMUSP, Dept Pediat, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Fis Sao Carlos, Sao Carlos, SP - Brazil

^[3] FMUSP, Grad Program Expt Pathophysiol, Sao Paulo, SP - Brazil

^[4] FMUSP, Dept Neurol, Sao Paulo, SP - Brazil

^[5] FMUSP, Hosp Clin, Clin Neurol Div, Sao Paulo, SP - Brazil

^[6] FMUSP, Hosp Clin, Epilepsy Surg Grp, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: PLoS One; v. 10, n. 5 MAY 26 2015.
• Web of Science Citations: 3

Abstract

Age at epilepsy onset has a broad impact on brain plasticity and epilepsy pathomechanisms. Prolonged febrile seizures in early childhood (FS) constitute an initial precipitating insult (IPI) commonly associated with mesial temporal lobe epilepsy (MTLE). FS-MTLE patients may have early disease onset, i.e. just after the IPI, in early childhood, or late-onset, ranging from mid-adolescence to early adult life. The mechanisms governing early (E) or late (L) disease onset are largely unknown. In order to unveil the molecular pathways underlying E and L subtypes of FS-MTLE we investigated global gene expression in hippocampal CA3 explants of FS-MTLE patients submitted to hippocampectomy. Gene coexpression networks (GCNs) were obtained for the E and L patient groups. A network-based approach for GCN analysis was employed allowing: i) the visualization and analysis of differentially expressed (DE) and complete (CO) - all valid GO annotated transcripts - GCNs for the E and L groups; ii) the study of interactions between all the system's constituents based on community detection and coarse-grained community structure methods. We found that the E-DE communities with strongest connection weights harbor highly connected genes mainly related to neural excitability and febrile seizures, whereas in L-DE communities these genes are not only involved in network excitability but also playing roles in other epilepsy-related processes. Inversely, in E-CO the strongly connected communities are related to compensatory pathways (seizure inhibition, neuronal survival and responses to stress conditions) while in L-CO these communities harbor several genes related to pro-epileptic effects, seizure-related mechanisms and vulnerability to epilepsy. These results fit the concept, based on fMRI and behavioral studies, that early onset epilepsies, although impacting more severely the hippocampus, are associated to compensatory mechanisms, while in late MTLE development the brain is less able to generate adaptive mechanisms, what has implications for epilepsy management and drug discovery. (AU)

• FAPESP's process: 09/53443-1 - Neuroimmunology, functional genomics and neuroimaging: an integrated approach for studying physiopathology and treatment in refractory epilepsy
• Grantee: Carlos Alberto Moreira Filho
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 05/56446-0 - High resolutions structural MRI and receptor imaging studies in refractory temporal lobe epilepsy: in vivo and ex vivo analyses
• Grantee: Edson Amaro Junior
• Support type: Inter-institutional Cooperation in Support of Brain Research (CINAPCE) - Thematic Grants
• FAPESP's process: 11/50761-2 - Models and methods of e-Science for life and agricultural sciences
• Grantee: Roberto Marcondes Cesar Junior
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 05/00587-5 - Mesh (graph) modeling and techniques of pattern recognition: structure, dynamics and applications
• Grantee: Roberto Marcondes Cesar Junior
• Support type: Research Projects - Thematic Grants