Different mechanisms of hypersynchrony initiation lead to divergent transcriptome changes in the mouse forebrain
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE149754 | GEO | 2020/05/07
REPOSITORIES: GEO
Similar Datasets
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
Project description:Since many years, we are interested in the regulation of the intraneuronal chloride concentration. We were the first group reporting a full knockout of the KCl-co-transporter KCC2, which dies immediately after birth due to respiratory failure. Notably, KCC2 loss-of-function mutations are associated with inherited febrile seizures, severe genetic generalized epilepsy and epilepsy of infancy with migrating focal seizures. Here, we used our floxed line to study the consequences of the disruption of KCC2 within parvalbumin-positive interneurons in mice. Remarkably, this leads to the disinhibition of PV-positive interneurons as evidenced by a decrease of E-S-Coupling and an increase in the sIPSC frequency. Nevertheless, these mice develop fatal epilepsy with progressive loss of parvalbumin-positive interneurons thus increasing network excitability.
2022-11-02 | E-MTAB-11147 | biostudies-arrayexpress
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. Keywords: time-course
2004-10-14 | GSE1834 | GEO
Project description:Early childhood convulsions have been correlated with hippocampal neuron loss in patients with intractable temporal lobe epilepsy. Using a "two-hit" rat seizure model, we have shown that animals subjected to kainate (KA)- or hypoxia-induced seizures during early postnatal period showed no cell death, yet sustained more extensive neuronal death after second seizures in adulthood. An early life seizure, without causing overt cellular injury, predisposes the brain to the damaging effect of seizures in later life. Cellular and molecular changes that accompany early seizures and that lead to subsequent epileptogenesis and increased susceptibility to seizure-induced neuronal injury, however, remain poorly understood. We propose to investigate age-specific, time-dependent changes in gene expression that may underlie this priming effect of early-life seizures. We will determine the sequence of gene expression pattern in the hippocampus at various times following KA induced seizures at postnatal day (P) 15. Previous studies have shown that AMPA receptor subtype of glutamate receptors play a crucial role in the age-specific vulnerability and in the long-term epileptogenic effects of perinatal hypoxia seizures. We found that AMPA receptor antagonists block the increased susceptibility caused by early life seizures to later seizures and seizure-induced brain damage. We hypothesize that an alteration of AMPA receptor composition is one of many changes caused by early-life seizures that leads to an increase in Ca2+ permeability, which then results in cascade of downstream events and modifies array of gene expression that promote epileptogenesis and susceptibility to neuronal death in later life. We will examine three time points: 1hr, 72 hr, and 15 days following systemic KA-induced seizures at P15 as we have previously observed structural changes within the hippocampus at these time points. Within an hour of KA seizures, a marked swelling of dendrites, disassembly of dendritic microtubules and glycogen depletion are observed by electron microscopy. Within 5 days, basal dendrites of CA3 hippocampal pyramidal neurons show abnormal spine morphology and decreased branching pattern. 15 days after the seizures, aberrant growth of mossy fibers in the CA3 stratum oriens is observed in animals exposed to KA. Ten hippocampi will be pooled from five animals treated with KA (3mg/kg i.p.) and from five littermate controls injected with PBS. Animals will be decapitated and hippocampi will be rapidly dissected from the brain, flash frozen in liquid nitrogen, and stored at -80C until extraction of total RNA, which will be sent to the center. We will provide 4 tissue samples-2 controls and 2 KA, each a pool of five animals - for each time points. Mixing tissues from multiple rats will normalize single nucleotide polymorphisms and tissue heterogeneity.
2008-06-11 | E-GEOD-1831 | biostudies-arrayexpress
Project description:∆FosB epigenetically regulates target gene expression; however, whether ∆FosB targets the same genes when induced by recurrent seizures in different neurological conditions like Alzheimer's disease (AD) is unclear. We performed hippocampal ChIP-sequencing to identify ∆FosB target genes in APP mice, a model of AD, and in pilocarpine-treated wildtype mice (Pilo mice), a model of epilepsy. Functional domains modulated by ∆FosB target genes are expanded and diversified in APP mice and in Pilo mice (vs respective controls), and primarily involve neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and immunity. To identify genes bound by ∆FosB regardless of seizure etiology, we focused on the 442 ∆FosB target genes in both APP and Pilo mice (not respective controls), which related to pathways including membrane potential regulation, glutamatergic signaling, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and RT-qPCR in independent mice detected altered expression of several ∆FosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced ∆FosB can bind genes in seizure etiology-dependent patterns, but can also bind genes in patterns regardless of seizure etiology. Understanding factors that influence ∆FosB binding patterns could reveal novel insights into control of gene expression in disorders with recurrent seizures.
2020-04-16 | E-MTAB-8954 | biostudies-arrayexpress
Project description:∆FosB epigenetically regulates target gene expression; however, whether ∆FosB targets the same genes when induced by recurrent seizures in different neurological conditions like Alzheimer's disease (AD) is unclear. We performed hippocampal ChIP-sequencing to identify ∆FosB target genes in APP mice, a model of AD, and in pilocarpine-treated wildtype mice (Pilo mice), a model of epilepsy. Functional domains modulated by ∆FosB target genes are expanded and diversified in APP mice and in Pilo mice (vs respective controls), and primarily involve neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and immunity. To identify genes bound by ∆FosB regardless of seizure etiology, we focused on the 442 ∆FosB target genes in both APP and Pilo mice (not respective controls), which related to pathways including membrane potential regulation, glutamatergic signaling, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and RT-qPCR in independent mice detected altered expression of several ∆FosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced ∆FosB can bind genes in seizure etiology-dependent patterns, but can also bind genes in patterns regardless of seizure etiology. Understanding factors that influence ∆FosB binding patterns could reveal novel insights into control of gene expression in disorders with recurrent seizures.
2020-04-16 | E-MTAB-8963 | biostudies-arrayexpress
Project description:Early childhood convulsions have been correlated with hippocampal neuron loss in patients with intractable temporal lobe epilepsy. Using a "two-hit" rat seizure model, we have shown that animals subjected to kainate (KA)- or hypoxia-induced seizures during early postnatal period showed no cell death, yet sustained more extensive neuronal death after second seizures in adulthood. An early life seizure, without causing overt cellular injury, predisposes the brain to the damaging effect of seizures in later life. Cellular and molecular changes that accompany early seizures and that lead to subsequent epileptogenesis and increased susceptibility to seizure-induced neuronal injury, however, remain poorly understood. We propose to investigate age-specific, time-dependent changes in gene expression that may underlie this priming effect of early-life seizures. We will determine the sequence of gene expression pattern in the hippocampus at various times following KA induced seizures at postnatal day (P) 15. Previous studies have shown that AMPA receptor subtype of glutamate receptors play a crucial role in the age-specific vulnerability and in the long-term epileptogenic effects of perinatal hypoxia seizures. We found that AMPA receptor antagonists block the increased susceptibility caused by early life seizures to later seizures and seizure-induced brain damage. We hypothesize that an alteration of AMPA receptor composition is one of many changes caused by early-life seizures that leads to an increase in Ca2+ permeability, which then results in cascade of downstream events and modifies array of gene expression that promote epileptogenesis and susceptibility to neuronal death in later life. We will examine three time points: 1hr, 72 hr, and 15 days following systemic KA-induced seizures at P15 as we have previously observed structural changes within the hippocampus at these time points. Within an hour of KA seizures, a marked swelling of dendrites, disassembly of dendritic microtubules and glycogen depletion are observed by electron microscopy. Within 5 days, basal dendrites of CA3 hippocampal pyramidal neurons show abnormal spine morphology and decreased branching pattern. 15 days after the seizures, aberrant growth of mossy fibers in the CA3 stratum oriens is observed in animals exposed to KA. Ten hippocampi will be pooled from five animals treated with KA (3mg/kg i.p.) and from five littermate controls injected with PBS. Animals will be decapitated and hippocampi will be rapidly dissected from the brain, flash frozen in liquid nitrogen, and stored at -80C until extraction of total RNA, which will be sent to the center. We will provide 4 tissue samples-2 controls and 2 KA, each a pool of five animals - for each time points. Mixing tissues from multiple rats will normalize single nucleotide polymorphisms and tissue heterogeneity. Keywords: time-course
2004-10-14 | GSE1831 | GEO
Project description:Status Epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report an unbiased analysis of the hippocampal transcriptome of mice with targeted disruption of Dio2 in the astrocytes (Astro-D2KO mouse) undergoing 3 h SE.
2018-05-25 | GSE114887 | GEO
Project description:This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE). A consecutive series of sixteen patients with refractory temporal lobe epilepsy was studied. Based on a median baseline seizure frequency of 2.0 seizures per month, low versus high seizure frequency was defined as < 2 seizures/month and > 2 seizures/month, respectively.
2022-11-15 | GSE217726 | 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
2007-12-26 | GSE6614 | GEO