title: Community structure analysis of transcriptional networks reveals distinct molecular pathways for early- and late-onset temporal lobe epilepsy with childhood febrile seizures.
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.
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Moreira-Filho
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Silvia Yumi
authors.initials: SY
authors.lastname: Bando
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Fernanda Bernardi
authors.initials: FB
authors.lastname: Bertonha
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Priscila
authors.initials: P
authors.lastname: Iamashita
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil.
authors.forename: Filipi Nascimento
authors.initials: FN
authors.lastname: Silva
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil.
authors.forename: Luciano da Fontoura
authors.initials: Lda F
authors.lastname: Costa
authors.affiliation: Graduate Program on Experimental Pathophysiology, FMUSP, São Paulo, SP, Brazil.
authors.forename: Alexandre Valotta
authors.initials: AV
authors.lastname: Silva
authors.affiliation: Department of Neurology, FMUSP, São Paulo, SP, Brazil; Clinical Neurology Division, Hospital das Clínicas, FMUSP, São Paulo, SP, Brazil.
authors.forename: Luiz Henrique Martins
authors.initials: LH
authors.lastname: Castro
authors.affiliation: Epilepsy Surgery Group, Hospital das Clínicas, FMUSP, São Paulo, SP, Brazil.
authors.forename: Hung-Tzu
authors.initials: HT
authors.lastname: Wen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D003294:Seizures, Febrile / Q000235:genetics*; D055815:Young Adult