Project description:Most patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) have hippocampal sclerosis on the postoperative histopathological examination. Although most patients with MTLE do not refer to a family history of the disease, familial forms of MTLE have been reported. We studied surgical specimens from patients with MTLE who had epilepsy surgery for medically intractable seizures. We assessed and compared messenger RNA (mRNA) expression profiles of the tissue lesion found in patients with familial MTLE (n = 3) and sporadic MTLE (n = 5). In addition, we used data from control hippocampi obtained from a public database (n = 7). We obtained expression profiles using the Human Genome U133 Plus 2.0 (Affymetrix) microarray platform. Overall, the molecular profile identified in familial MTLE was distinct from that found in sporadic MTLE. In the tissue of patients with familial MTLE, we found an over-representation of the biological pathways related to protein response, mRNA processing, and synaptic plasticity and function. In sporadic MTLE, the gene expression profile suggests that the inflammatory response is highly activated. We also found enrichment of gene sets involved in inflammatory cytokines and mediators and chemokine receptor pathways in both groups. However, in sporadic MTLE, we also found enrichment of epidermal growth factor signaling, prostaglandin synthesis and regulation, and microglia pathogen phagocytosis pathways. Furthermore, based on the gene expression signatures, we identified different potential compounds to treat patients with familial and sporadic MTLE. To our knowledge, this is the first study assessing the mRNA profile in surgical tissue obtained from patients with familial MTLE and comparing it with sporadic MTLE. Our results clearly show that, despite phenotypic similarities, both forms of MTLE present distinct molecular signatures, thus suggesting different underlying molecular mechanisms that may require distinct therapeutic approaches.

Project description:Mesial Temporal Lobe Epilepsy (MTLE) is a chronic disease characterized by recurrent unprovoked partial seizures. Current treatments lack long-term efficacy and typically act only to ameliorate the symptomology, rather than to modify the course of the disease. Chronic kainic acid (KA)-induced models of MTLE mimic prominent histopathological and electroencephalographic features of human MTLE, including hippocampal sclerosis, CA1 neuronal loss, astrogliosis, microgliosis, and electrographic hippocampal discharges. Here we examined the transcriptional profiles of the hippocampus of KA - vs sham-injected mice from epileptogenesis to the stabilization of spontaneous recurring seizures. KA (1 nmol) or saline (sham) was injected unilaterally into the dorsal hippocampus of 12 week old C57BL/6J mice, and the ipsilateral (IL) and contralateral (CL) hippocampi were isolated for whole-genome expression profiling (Illumina microarray) or immunohistochemistry 7, 28 and 60 d later. Differential gene expression analysis of the IL hippocampus indicated that 1349, 484, and 439 genes were significantly (fdr<0.05) altered in KA compared to sham at 7, 28 and 60 d, respectively. 108 genes were altered at all time-points assessed, while others were altered in a time-dependent manner, indicative of distinct hippocampal gene expression profiles across the course of disease. Ingenuity Pathway Analysis revealed that specific immune cell and inflammatory signaling pathways were upregulated at 7 and 28 d, in support of a role of neuroinflammation in the disease etiology. The top canonical pathways profile at 60 d was quite distinct from that at 7 and 28 d, although certain inflammatory pathways were still prevalent, indicative of pathways involved in the maintenance of the disease. Consistent with a role of neuroinflammation in MTLE, immunohistochemical analyses demonstrated time-dependent changes in both the intensity of immunoreactivity and number of Iba1- and GFAP-positive cells. To reveal gene networks not apparent with differential expression data alone, weighted gene co-expression analysis (WGCNA) was performed. A gene network that highly associated with 7 d IL-KA (but not 28 and 60 d) was identified, which may point to changes involved in the process of epileptogenesis. Another gene network revealed a group of genes highly associated with changes occurring at 28 and 60 d, but not 7 d, which may point to molecules involved in the generation of spontaneous recurring seizures. Collectively, results indicate that specific pathways, including many associated with neuroinflammation, are activated in a time-dependent manner in MTLE.

Project description:The epilepsies represent one of the most common neurological disorders. Mesial temporal lobe epilepsies (MTLE) are the most frequent form of partial epilepsies and display frequent resistance to anti-epileptic drugs thus representing a major health care problem. In TLE, the origin of seizure activity typically involves the hippocampal formation, which displays major neuropathological features, described with the term hippocampal sclerosis (HS). HS is the most frequent pathological substrate of refractory mesial temporal lobe epilepsy. Complex partial seizures (CPS) are the predominant seizure type associated with medial temporal lobe epilepsy. MTLE is commonly due to mesial temporal sclerosis (MTS). The biology underlying the epilepstic seizures and the transcriptome associated to the seizure in intractable medial temporal lobe epilepsy is ill understood. The aim of the study was to identify potential biomarkers that could identify epileptic seizure. Thus we performed transcriptome profiling of ten medial temporal lobe epilepsy cases which are resistant to the drug and underwent temporal lobectomy. The cases constitutes of patients with intractable complex partial seizure, treated medically and have undergone detailed presurgical evaluation and subjected to surgery for standard temporal lobectomy and amygdalo-hippocampectomy. The spiking areas identified after the electrocorticography will form the test tissues, which compared with the nonspiking areas removed during the surgery, from the same patient. This could probably form one of the appropriate controls, as test and control are from same patient, which eliminates the genome variations that could incur due to the comparison with the tissues from the another patient. Also this could get rid of expression changes due to the treatments undergone by the patient. We performed two color microarray wherein we labled seizure focus (spiking area) with Cy5 and non-seizure region tissues (non-spiking) with Cy3. As a strategy to test the possibility of potential diagnostic biomarkers we are intended to test the differentially regulated molecules in an independent set of epilepsy samples. Two color experiment

Project description:The epilepsies represent one of the most common neurological disorders. Mesial temporal lobe epilepsies (MTLE) are the most frequent form of partial epilepsies and display frequent resistance to anti-epileptic drugs thus representing a major health care problem. In TLE, the origin of seizure activity typically involves the hippocampal formation, which displays major neuropathological features, described with the term hippocampal sclerosis (HS). HS is the most frequent pathological substrate of refractory mesial temporal lobe epilepsy. Complex partial seizures (CPS) are the predominant seizure type associated with medial temporal lobe epilepsy. MTLE is commonly due to mesial temporal sclerosis (MTS). The biology underlying the epilepstic seizures and the transcriptome associated to the seizure in intractable medial temporal lobe epilepsy is ill understood. The aim of the study was to identify potential biomarkers that could identify epileptic seizure. Thus we performed transcriptome profiling of ten medial temporal lobe epilepsy cases which are resistant to the drug and underwent temporal lobectomy. The cases constitutes of patients with intractable complex partial seizure, treated medically and have undergone detailed presurgical evaluation and subjected to surgery for standard temporal lobectomy and amygdalo-hippocampectomy. The spiking areas identified after the electrocorticography will form the test tissues, which compared with the nonspiking areas removed during the surgery, from the same patient. This could probably form one of the appropriate controls, as test and control are from same patient, which eliminates the genome variations that could incur due to the comparison with the tissues from the another patient. Also this could get rid of expression changes due to the treatments undergone by the patient. We performed two color microarray wherein we labled seizure focus (spiking area) with Cy5 and non-seizure region tissues (non-spiking) with Cy3. As a strategy to test the possibility of potential diagnostic biomarkers we are intended to test the differentially regulated molecules in an independent set of epilepsy samples.

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Sub-compartment specific small non-coding RNA expression deregulation and altered nucleoli in mesial temporal lobe epilepsy

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