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.
Highlights
Mesial temporal lobe epilepsy with childhood febrile seizures (FS-mesial temporal lobe epilepsy (MTLE)) is a distinctive entity that can be delineated from afebrile MTLE as demonstrated by epidemiological [1], radiological [2], and genomic [3, 4] studies
We developed a network methodology for Gene coexpression networks (GCNs) visualization (3D) and analysis [4] that allows the categorization of network nodes according to node-centered connectivity taken along distinct hierarchical levels of gene-gene neighborhoods [36, 37]: hubs are highly connected nodes, VIPs—standing for “Very Important Person”, an acronym initially coined for the study of social networks [38] and equivalent to the term “date-hubs” in biological network papers [39]—have low node degree but connect only with hubs, and high-hubs have VIP status and high overall number of connections
Community detection analysis of modular transcriptional repertoires for DE and CO gene coexpression networks, and the subsequent coarse-grained community structure (CGCS) data analysis, revealed distinct molecular pathways for early- and late-onset forms of MTLE associated with childhood febrile seizures, as discussed below
Summary
Mesial temporal lobe epilepsy with childhood febrile seizures (FS-MTLE) is a distinctive entity that can be delineated from afebrile MTLE as demonstrated by epidemiological [1], radiological [2], and genomic [3, 4] studies. The predisposition to developing temporal lobe epilepsy and hippocampal sclerosis has been investigated in animal models of FS induced by hyperthermia and in prospective clinical studies of children with FSE. These studies revealed that FS development and subsequent epilepsy results from a combination of environmental and genetic factors that vary in each individual [13, 20, 21]. In order to investigate this issue, gene expression data was analyzed using network science parameters, i.e. with emphasis in complex network visualization, gene hierarchy categorization, community detection and coarse-grained community structure [4, 26, 31, 32]
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