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


RESULTS
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
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.
Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Silvia Y
SY
Bando
Maryana C
MC
Alegro
Edson
E
Amaro
Alexandre V
AV
Silva
Luiz H M
LH
Castro
Hung-Tzu
HT
Wen
Leandro de A
Lde A
Lima
Helena
H
Brentani
Carlos Alberto
CA
Moreira-Filho
D000293:Adolescent; D000328:Adult; D056654:CA3 Region, Hippocampal / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D003294:Seizures, Febrile / Q000150:complications / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics*; D055815:Young Adult