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Hippocampal CA3 transcriptome signature correlates with initial precipitating injury in refractory mesial temporal lobe epilepsy.

ABSTRACT: 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.

SUBMITTER: Bando SY

PROVIDER: S-EPMC3194819 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Hippocampal CA3 transcriptome signature correlates with initial precipitating injury in refractory mesial temporal lobe epilepsy.

Bando Silvia Y SY Alegro Maryana C MC Amaro Edson E Silva Alexandre V AV Castro Luiz H M LH Wen Hung-Tzu HT Lima Leandro de A Lde A Brentani Helena H Moreira-Filho Carlos Alberto CA

PloS one 20111014 10

<h4>Background</h4>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 ...[more]

PMID: 22022585

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Project description:ObjectivesInitial precipitating injury (IPI) such as febrile convulsion and intracranial infection will increase the susceptibility to epilepsy. It is still unknown if the functional deficits differ between mesial temporal lobe epilepsy with IPI (mTLE-IPI) and without IPI (mTLE-NO).MethodsWe recruited 25 mTLE-IPI patients, 35 mTLE-NO patients and 33 healthy controls (HC). Static regional homogeneity (sReHo) and dynamic regional homogeneity (dReHo) were then adopted to estimate the alterations of local neuronal activity. One-way analysis of variance was used to analyze the differences between the three groups in sReHo and dReHo. Then the results were utilized as masks for further between-group comparisons. Besides, correlation analyses were carried out to detect the potential relationships between abnormal regional homogeneity indicators and clinical characteristics.ResultsWhen compared with HC, the bilateral thalamus and the visual cortex in mTLE-IPI patients showed an increase in both sReHo and variability of dReHo. Besides, mTLE-IPI patients exhibited decreased sReHo in the right cerebellum crus1/crus2, inferior parietal lobule and temporal neocortex. mTLE-NO patients showed decreased sReHo and variability of dReHo in the bilateral temporal neocortex compared with HC. Increased sReHo and variability of dReHo were found in the bilateral visual cortex when mTLE-IPI patients was compared with mTLE-NO patients, as well as increased variability of dReHo in the left thalamus and decreased sReHo in the right dorsolateral prefrontal cortex. Additionally, we discovered a negative correlation between the national hospital seizure severity scale testing score and sReHo in the right cerebellum crus1 in mTLE-IPI patients.ConclusionAccording to the aforementioned findings, both mTLE-IPI and mTLE-NO patients had significant anomalies in local neuronal activity, although the functional deficits were much severer in mTLE-IPI patients. The use of sReHo and dReHo may provide a novel insight into the impact of the presence of IPI on the development of mTLE.

Dataset Information

Hippocampal CA3 transcriptome signature correlates with initial precipitating injury in refractory mesial temporal lobe epilepsy.

Publications

Hippocampal CA3 transcriptome signature correlates with initial precipitating injury in refractory mesial temporal lobe epilepsy.

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