Dataset Information

Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy.

ABSTRACT: We previously described - studying transcriptional signatures of hippocampal CA3 explants - that febrile (FS) and afebrile (NFS) forms of refractory mesial temporal lobe epilepsy constitute two distinct genomic phenotypes. That network analysis was based on a limited number (hundreds) of differentially expressed genes (DE networks) among a large set of valid transcripts (close to two tens of thousands). Here we developed a methodology for complex network visualization (3D) and analysis that allows the categorization of network nodes according to distinct hierarchical levels of gene-gene connections (node degree) and of interconnection between node neighbors (concentric node degree). Hubs are highly connected nodes, VIPs have low node degree but connect only with hubs, and high-hubs have VIP status and high overall number of connections. Studying the whole set of CA3 valid transcripts we: i) obtained complete transcriptional networks (CO) for FS and NFS phenotypic groups; ii) examined how CO and DE networks are related; iii) characterized genomic and molecular mechanisms underlying FS and NFS phenotypes, identifying potential novel targets for therapeutic interventions. We found that: i) DE hubs and VIPs are evenly distributed inside the CO networks; ii) most DE hubs and VIPs are related to synaptic transmission and neuronal excitability whereas most CO hubs, VIPs and high hubs are related to neuronal differentiation, homeostasis and neuroprotection, indicating compensatory mechanisms. Complex network visualization and analysis is a useful tool for systems biology approaches to multifactorial diseases. Network centrality observed for hubs, VIPs and high hubs of CO networks, is consistent with the network disease model, where a group of nodes whose perturbation leads to a disease phenotype occupies a central position in the network. Conceivably, the chance for exerting therapeutic effects through the modulation of particular genes will be higher if these genes are highly interconnected in transcriptional networks.

SUBMITTER: Bando SY

PROVIDER: S-EPMC3836787 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy.

Bando Silvia Yumi SY Silva Filipi Nascimento FN Costa Luciano da Fontoura Lda F Silva Alexandre V AV Pimentel-Silva Luciana R LR Castro Luiz Hm LH Wen Hung-Tzu HT Amaro Edson E Moreira-Filho Carlos Alberto CA

PloS one 20131121 11

We previously described - studying transcriptional signatures of hippocampal CA3 explants - that febrile (FS) and afebrile (NFS) forms of refractory mesial temporal lobe epilepsy constitute two distinct genomic phenotypes. That network analysis was based on a limited number (hundreds) of differentially expressed genes (DE networks) among a large set of valid transcripts (close to two tens of thousands). Here we developed a methodology for complex network visualization (3D) and analysis that allo ...[more]

PMID: 24278214

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Project description:BACKGROUND: Prolonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). In order to investigate IPI influence on the transcriptional phenotype underlying RMTLE we comparatively analyzed the transcriptomic signatures of CA3 explants surgically obtained from RMTLE patients with (FS) or without (NFS) febrile seizure history. Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations. METHODOLOGY/PRINCIPAL FINDINGS: DNA microarray analysis revealed that CA3 global gene expression differed significantly between FS and NFS subgroups. An integrative functional genomics methodology was used for characterizing the relations between GO biological processes themes and constructing transcriptional interaction networks defining the FS and NFS transcriptomic signatures and its major gene-gene links (hubs). Co-expression network analysis showed that: i) CA3 transcriptomic profiles differ according to the IPI; ii) FS distinctive hubs are mostly linked to glutamatergic signalization while NFS hubs predominantly involve GABAergic pathways and neurotransmission modulation. Both networks have relevant hubs related to nervous system development, what is consistent with cell genesis activity in the hippocampus of RMTLE patients. Moreover, two candidate genes for therapeutic targeting came out from this analysis: SSTR1, a relevant common hub in febrile and afebrile transcriptomes, and CHRM3, due to its putative role in epilepsy susceptibility development. MRI texture analysis allowed an overall accuracy of 90% for pixels correctly classified as belonging to FS or NFS groups. Histological examination revealed that granule cell loss was significantly higher in FS hippocampi. CONCLUSIONS/SIGNIFICANCE: CA3 transcriptional signatures and dentate gyrus morphology fairly correlate with IPI in RMTLE, indicating that FS-RMTLE represents a distinct phenotype. These findings may shed light on the molecular mechanisms underlying refractory epilepsy phenotypes and contribute to the discovery of novel specific drug targets for therapeutic interventions.

Project description:OBJECTIVE:The current practice under which patients with refractory epilepsy are surgically treated is based mainly on the identification of specific cortical areas, mainly the epileptogenic zone, which is believed to be responsible for generation of seizures. A better understanding of the whole epileptic network and its components and properties is required before more effective and less invasive therapies can be developed. The aim of the present study was to partially characterize the evolution of the functional network during the preictal-ictal transition in partial seizures in patients with temporal lobe epilepsy (TLE). METHODS:Scalp and foramen ovale (FOE) recordings from twenty-two TLE patients were analyzed under the complex network perspective. The density of links, average path length, average clustering coefficient, and modularity were calculated during the preictal and the ictal stages. Both linear-Pearson correlation-and non-linear-phase synchronization-measures were used as proxies of functional connectivity between the electrode locations areas. The transition from one stage to the other was evaluated in the whole network and in the mesial sub-networks. The results were compared with a voltage-dependent measure, namely, the spectral entropy. RESULTS:Changes in the global functional network during the transition from the preictal to the ictal stage show, in the linear case, that in sixteen cases (72.7%) the density of the links increased during the seizure, with a decrease in the average path length in fifteen cases (68.1%). There was also a preictal and ictal imbalance in functional connectivity during both stages (77.2% to 86.3%). The SE dropped during the seizure in 95.4% of the cases, but did not show any tendency towards lateralization. When using the nonlinear measure of functional connectivity, the phase synchronization, similar results were obtained. CONCLUSIONS:In TLE patients, the transition to the ictal stage is accompanied by increasing global synchronization and a more ordered spectral content of the signals, indicated by lower spectral entropy. The interictal connectivity imbalance (lower ipsilateral connectivity) is sustained during the seizure, irrespective of any appreciable imbalance in the spectral entropy of the mesial recordings.

Dataset Information

Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy.

Publications

Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy.

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