Pilot Study Evaluating Everolimus Molecular Mechanisms in Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD)
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF-X, Q Exactive
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Beatrix Ueberheide
PROVIDER: MSV000088551 | MassIVE | Fri Dec 10 03:27:00 GMT 2021
REPOSITORIES: MassIVE
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Project description:Mesial temporal lobe epilepsy (MTLE) is the most common type of focal seizure disorder. In MTLE, seizures typically originate from a sclerotic hippocampus. Approximately one-third of patients do not respond to anti-seizure drugs and have few effective therapeutic options. Surgery to resect or ablate the affected temporal lobe is one such option, but it is not indicated or adequate for all individuals and can have adverse effects. Here, we report the development of an alternative cell therapy strategy for drug-resistant MTLE. The cell therapeutic is derived from a clinical-grade human embryonic stem cell line, and composed of cryopreserved post-mitotic medial ganglionic eminence (MGE)-type GABAergic inhibitory neurons of a predominantly pallial interneuron lineage. Single-dose intrahippocampal delivery of cryopreserved human pallial interneurons in a chronic mouse model of drug-resistant MTLE resulted in consistent and stable suppression of mesiotemporal seizures, with most animals becoming seizure-free. The grafted human interneurons distributed locally, matured, and persisted in the sclerotic hippocampus throughout the 8.5-month study. Pathological hallmarks of MTLE, such as hippocampal granule cell dispersion and sclerosis, were significantly reduced, and epileptic animal survival rates increased, after administration of the human interneurons. Suppression of seizure activity and amelioration of neuropathology were dose-dependent and suggested a broad therapeutic dosing range. No ectopic tissue or teratoma formation was detected after cell transplantation. Furthermore, behavioral abnormalities were not observed at any dose on a battery of assays. These findings support further development of human pallial MGE-type GABAergic interneuron cell therapy for the treatment of drug-resistant focal epilepsies.
2023-10-10 | GSE208672 | GEO
Project description:Focal cortical dysplasia (FCD), a focal brain malformation, is the most common cause of intractable epilepsy. One of the related disorders is tuberous sclerosis (TS). The dysplasia appears to result from a defect in cortical development, however, this disorder is heterogeneous, and FCD seizure therapy is non-specific and failure-prone. As a final recourse, patients may undergo multiple surgical resections to control seizures. Thus, there is a clinical need to characterize this disorder with respect to structural, molecular, and electrophysiological profiles, which will lead to development of animal models and pilot therapies that we will then apply to humans.
2015-06-01 | GSE62019 | GEO
Project description:Nicotine, acting through the neuronal nicotinic acetylcholine receptors (nAChR), can induce seizures in mice. We aimed to study brain transcriptional response to seizure and to identify genes whose expression is altered after nicotine-induced seizures. Whole brains of untreated mice were compared to brains one hour after seizure activity, using Affymetrix U74Av2 microaarays. Experimental groups included wild-type mice and both nicotine-induced seizures sensitive and resistant nAChR mutant mice. Each genotype group received different nicotine doses to generate seizures. This approach allowed the identification of significantly changed genes whose expression was dependent on seizure activity, nicotine administration or both, but not on the type of nAChR subunit mutation or the amount of nicotine injected. Significant expression changes were detected in 62 genes (p < 0.05, FDR correction). Among them, GO functional annotation analysis determined that the most significantly over-represented categories were of genes encoding MAP kinase phosphatases, regulators of transcription and nucleosome assembly proteins. In-silico bioinformatic analysis of the promoter regions of the 62 changed genes detected the significant enrichments of 16 transcription regulatory elements (TREs), creating a network of transcriptional regulatory responses to seizures. The TREs for ATF and SRF were most significantly enriched, supporting their association with seizure activity. Our data suggest that nicotine-induced seizure in mice is a useful model to study seizure activity and its global brain transcriptional response. The differentially expressed genes detected here can help understand the molecular mechanisms underlying seizures in animal models, and may also serve as candidate genes to study epilepsy in humans. Keywords: treatment, seizure activity, genotypes
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Project description:Microarray profiling was used to investigate gene expression in the hypoxic seizure model of acquired epilepsy in the rat, with the aim of characterizing functional pathways which are persistently activated or repressed during epileptogenesis. Hippocampal and cortical tissues were transcriptionally profiled over a one week period following an initial series of seizures induced by mild hypoxia at post-natal day 10 (P10), and the gene expression data was then analyzed with a focus on gene set enrichment analysis, an approach which emphasizes regulation of entire pathways rather than of individual genes. Animals were subjected to one of three conditions, control condition with no exposure to hypoxia, hypoxic seizures, and hypoxic seizures followed by treatment with the AMPAR antagonist NBQX, a compound tentatively proposed to be a modulator of epileptogenesis. Gene expression in the control samples was found to be consistent with known processes of neuronal maturation in the rat for the given time window. The hypoxic seizure response was found to be saliently enriched for components of the PI3K/mTOR and Wnt signaling pathways, alongside gene sets representative of glutamatergic, synaptic and axonal processes, perhaps regulated as a downstream consequence of activation of these pathways. Wnt signaling components were also found enriched in the more specifically epileptogenic NBQX-responsive gene set. While activation of the mTOR pathway is consistent with its known role in epileptogenesis and strengthens the case for mTOR or PI3K pathway inhibitors as potential anti-epileptogenic drugs, investigation of the role of Wnt signaling and the effect of cognate inhibitors offers a parallel avenue of research toward anti-epileptogenic treatment.
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Project description:Nicotine, acting through the neuronal nicotinic acetylcholine receptors (nAChR), can induce seizures in mice. We aimed to study brain transcriptional response to seizure and to identify genes whose expression is altered after nicotine-induced seizures. Whole brains of untreated mice were compared to brains one hour after seizure activity, using Affymetrix U74Av2 microaarays. Experimental groups included wild-type mice and both nicotine-induced seizures sensitive and resistant nAChR mutant mice. Each genotype group received different nicotine doses to generate seizures. This approach allowed the identification of significantly changed genes whose expression was dependent on seizure activity, nicotine administration or both, but not on the type of nAChR subunit mutation or the amount of nicotine injected. Significant expression changes were detected in 62 genes (p < 0.05, FDR correction). Among them, GO functional annotation analysis determined that the most significantly over-represented categories were of genes encoding MAP kinase phosphatases, regulators of transcription and nucleosome assembly proteins. In-silico bioinformatic analysis of the promoter regions of the 62 changed genes detected the significant enrichments of 16 transcription regulatory elements (TREs), creating a network of transcriptional regulatory responses to seizures. The TREs for ATF and SRF were most significantly enriched, supporting their association with seizure activity. Our data suggest that nicotine-induced seizure in mice is a useful model to study seizure activity and its global brain transcriptional response. The differentially expressed genes detected here can help understand the molecular mechanisms underlying seizures in animal models, and may also serve as candidate genes to study epilepsy in humans. Experiment Overall Design: Whole brain expression profiles were determined in two experimental groups of mice, sixteen mice that were not treated with nicotine and twelve mice one hour after experiencing nicotine-induced seizure. The untreated group included six wild-type mice, five alpha7+/T and five beta4-/- mice. The group of mice that underwent nicotine-induced seizures included three wild-types, five alpha7+/T and four beta4-/- mice. Different doses of nicotine were injected intraperitoneally (i.p.) to each genotype group of mice in order to achieve a similar seizure score in all three genotypes.
2008-04-09 | E-GEOD-6614 | biostudies-arrayexpress
Project description:Microarray profiling was used to investigate gene expression in the hypoxic seizure model of acquired epilepsy in the rat, with the aim of characterizing functional pathways which are persistently activated or repressed during epileptogenesis. Hippocampal and cortical tissues were transcriptionally profiled over a one week period following an initial series of seizures induced by mild hypoxia at post-natal day 10 (P10), and the gene expression data was then analyzed with a focus on gene set enrichment analysis, an approach which emphasizes regulation of entire pathways rather than of individual genes. Animals were subjected to one of three conditions, control condition with no exposure to hypoxia, hypoxic seizures, and hypoxic seizures followed by treatment with the AMPAR antagonist NBQX, a compound tentatively proposed to be a modulator of epileptogenesis. Gene expression in the control samples was found to be consistent with known processes of neuronal maturation in the rat for the given time window. The hypoxic seizure response was found to be saliently enriched for components of the PI3K/mTOR and Wnt signaling pathways, alongside gene sets representative of glutamatergic, synaptic and axonal processes, perhaps regulated as a downstream consequence of activation of these pathways. Wnt signaling components were also found enriched in the more specifically epileptogenic NBQX-responsive gene set. While activation of the mTOR pathway is consistent with its known role in epileptogenesis and strengthens the case for mTOR or PI3K pathway inhibitors as potential anti-epileptogenic drugs, investigation of the role of Wnt signaling and the effect of cognate inhibitors offers a parallel avenue of research toward anti-epileptogenic treatment. Cohorts of ten days old (P10) rat pups were subjected to one of three experimental conditions: 1) a control sham treatment inducing no hypoxic seizures (noHS), 2) a treatment under hypoxia inducing hypoxic seizures (HS), in which each animal underwent a 15 minutes passage at 5% O2, and 3) a treatment with hypoxia inducing hypoxic seizures, followed by four intra-peritoneal injections of NBQX over a 48 h period, starting at 30 minutes post-hypoxia (HS+NBQX). Control vehicle injections of DMSO were performed for the animals under the noHS and HS conditions. Time of occurrence and number of seizures for the animals undergoing hypoxia were recorded and analyzed. Times to the first seizure were found to be exponentially distributed, with mean time to first seizure of 114 seconds, and total count of seizures occurring in the 15 minute hypoxic interval was found to be approximately normally distributed, with mean count 10.6 and standard deviation 2.9. For each treatment condition, cohorts of 4 to 6 rat pups were killed at five sampling times spanning 1 hour to 1 week post-hypoxia (1h, 6h, 12h, 48h, 168h post-hypoxia), for a total of 75 animals sacrificed. Whole cortex and hippocampi were extracted from the sacrificed animals and separately profiled on two Affymetrix high-throughput plate microarrays after RNA quality control, resulting in a total of 144 CEL files encapsulating the gene expression data. The 144 CEL files, generated from scans of the individual microarrays on the two 96-well Affymetrix HT Rat Focus Arrays, were processed according to the MAS5 algorithm, resulting for each input CEL file in output of 24,249 probeset-level intensities and corresponding absent/present calls. For each processed scan, two summary statistics, consisting of the total number of present calls on the chip, and the 75th percentile of present call intensities, were then computed. A quality control step was performed by inspecting for outlier scans in the space of these two statistics (no outliers were found). Additional visual inspection of a heat map of clustered profiles identified a potential tissue assignment swap between two samples, which were conservatively eliminated from further analysis. The resulting 142 quality-controlled profiles were then assembled into a single data matrix, and normalized to each other by linear rescaling of all probeset intensities so as to bring the 75th percentile of present call intensities on all chips to a single common value. These processing steps, and most of the subsequent analyses discussed here, were done using the Gecko gene expression analysis platform (Theilhaber et al., 2004). Additional analyses were performed using the R statistical tools framework (R Development Core Team 2008).
2013-03-06 | E-GEOD-44903 | biostudies-arrayexpress
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2023-11-27 | GSE241525 | GEO
Project description:Despite recent advances in our understanding of synaptic transmission associated with epileptogenesis, the molecular mechanisms that control seizure frequency in patients with temporal lobe epilepsy (TLE) remain obscure. RNA-Seq was performed on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. Differential expression (DE) analysis of individuals with low (LSF, mean= 4 seizure/month) versus high (HSF, mean= 60 seizures/month) seizure frequency identified 979 genes with ≥2-fold change in transcript abundance (FDR-adjusted p-value <0.05). Comparisons with post-mortem controls revealed a large number of downregulated genes in the HSF (1,676) versus LSF (399) groups. More than 50 signaling pathways were inferred to be deactivated or activated, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both groups, key neuronal system pathways were systematically deactivated in the HSF group, including calcium, CREB and Opioid signaling. We also infer that enhanced expression of a signaling cascade promoting synaptic downscaling may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE.
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Project description:Mesial temporal lobe epilepsy (MTLE) is the most common medically refractory epilepsy syndrome; kainic acid (KA) induced seizures have been studied as a MTLE model as limbic seizures produced by systemic injections of KA result in a distinctive pattern of neurodegeneration in the hippocampus that resembles human hippocampal sclerosis. In our "2-hit" seizure model, animals subjected to seizures during week 2 of life become more susceptible to seizures later in life and sustain extensive hippocampal neuronal injury after second KA seizures in adulthood. Using high-density oligonucleotide gene arrays, we began to elucidate the molecular basis of this priming effect of early-life seizures and of the age-specific neuroprotection against seizure-induced neuronal injury. We seek to identify target genes for epileptogenesis and cell death by selecting transcripts that are differentially regulated at various times in the P15 and P30 hippocampus. To screen for and identify candidate genes responsible for epileptogenesis and seizure-induced cell death. We hypothesize that active process of cell death signaling and long-term synaptic changes leading to chronic epilepsy is mediated by distinct transcriptional responses in mature brain that are different from those in immature brain. We will select for transcripts that are highly regulated at 1, 6, 24, 72 and 240 hours (h) after KA-induced seizures at P30 compared to P15. These differentially regulated genes will serve as potential target genes for therapeutic intervention. Highly regulated genes identified in our array analysis will then be confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Causative roles of select genes will be directly tested by gene silencing using RNA interference technology or by gene delivery using viral vectors.
2008-06-11 | E-GEOD-1834 | biostudies-arrayexpress