Photothrombotic Cerebral Stroke as a Model of Post-Stroke Seizures/Epilepsy in aged mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE241528 | GEO | 2023/11/27
REPOSITORIES: GEO
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Project description:Stroke is a prevalent disorder representing the third leading cause of death and major cause of disability. Post-stroke epilepsy (PSE) has been recognized as a common clinical issue after stroke, accounting for 30-40% of the causes of epilepsy among older adults. In this study, we determined GABAA receptor-mediated seizure susceptibility after PT cerebral stroke in aged mice. Young adult mice around 10 weeks of age are widely used in stroke experiments. However, as most strokes are diagnosed in the elderly and PSE has been recognized as a common clinical incidence after stroke, we utilized photothrombosis (PT) model of cerebral ischemia and examined seizure susceptibility. To investigate in vitro drug-induced seizure susceptibility (E/I imbalance) of GABAA receptor antagonist, gabazine (GZ), voltage-sensitive dye (VSD) imaging techniques were used in hippocampal brain slices. One month after PT stroke, in vivo aged PT stroke mice exhibited severe convulsive seizures (late-onset). in vitro GZ-induced E/I imbalance in hippocampus of aging mice increased compared to young adults. In addition, Anti-seizure medication (levetiracetam) normalized in vitro GZ-induced E/I imbalance in hippocampus of aging mice. These findings exhibited that GABAA receptor-mediated seizures susceptibility (E/I imbalance) in hippocampus after cortical PT stroke in aging mice, but not in young adults.
2023-11-27 | GSE241525 | GEO
Project description:Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically-induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Ago-precipitated, synaptic vesicle target-enriched or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic anti-inflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented non-convulsive seizures, accompanied by forebrain accumulation of the convulsive seizures-mediating miR-134. RNA-sequencing demonstrated in doxycycline-treated dTg-211 cortices over-representation of synaptic activity, Ca2+ transmembrane transport, TGFβR-II signaling and cholinergic synapse pathways. Additionally, a cholinergic dis-regulated mouse model over-expressing a miR-refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hyper-synchronization, non-convulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.
2017-05-26 | GSE99307 | GEO
Project description:Severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome (DS), is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development, and persistent drug-resistant seizures. One of its primary monogenic causes is a mutation in SCN1A (Nav1.1), a type I voltage-gated sodium channel. In mice, Nav1.1 mutation is associated with reduced sodium current, altered interneuron firing, cognitive deficits, autistic-like traits and seizures. Here we describe a larval zebrafish Nav1.1 mutant that recapitulates salient features of the human SCN1A mutation phenotype. Between three and seven days post-fertilization, Nav1.1 mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviors. Transcriptomic analysis of Nav1.1 mutants was remarkable for the relatively small fraction of genes that were differentially expressed (~2%) and the lack of compensatory changes in expression for other SCN subunits. Pharmacological studies confirmed an antiepileptic action for the ketogenic diet, benzodiazepine, valproate, potassium bromide and stiripentol in Nav1.1 mutants; acetazolamide, phenytoin, ethosuximide had no effect, carbamazepine and vigabatrin made seizures worse. Using this mutant, we screened a chemical library of 320 compounds and identified four compounds that reduced spontaneous seizure-like behavior and one compound (clemizole) that inhibited convulsive behavior and electrographic seizures. Drug-resistant scn1a zebrafish mutants described here represent a new direction in modeling pediatric epilepsy and could be used to identify novel lead compounds for DS patients 4 Control sibling samples (sample= 10 pooled larvae) and 4 Nav1.1 mutants (sample= 10 pooled larvae) were collected at 6 dpf (days post fertilization). The Nav1.1 mutants were selected based on phenotype (dark color).
2014-01-04 | E-GEOD-43312 | biostudies-arrayexpress
Project description:Severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome (DS), is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development, and persistent drug-resistant seizures. One of its primary monogenic causes is a mutation in SCN1A (Nav1.1), a type I voltage-gated sodium channel. In mice, Nav1.1 mutation is associated with reduced sodium current, altered interneuron firing, cognitive deficits, autistic-like traits and seizures. Here we describe a larval zebrafish Nav1.1 mutant that recapitulates salient features of the human SCN1A mutation phenotype. Between three and seven days post-fertilization, Nav1.1 mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviors. Transcriptomic analysis of Nav1.1 mutants was remarkable for the relatively small fraction of genes that were differentially expressed (~2%) and the lack of compensatory changes in expression for other SCN subunits. Pharmacological studies confirmed an antiepileptic action for the ketogenic diet, benzodiazepine, valproate, potassium bromide and stiripentol in Nav1.1 mutants; acetazolamide, phenytoin, ethosuximide had no effect, carbamazepine and vigabatrin made seizures worse. Using this mutant, we screened a chemical library of 320 compounds and identified four compounds that reduced spontaneous seizure-like behavior and one compound (clemizole) that inhibited convulsive behavior and electrographic seizures. Drug-resistant scn1a zebrafish mutants described here represent a new direction in modeling pediatric epilepsy and could be used to identify novel lead compounds for DS patients
2014-01-04 | GSE43312 | 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:Neurodegenerative brain disorders become more common in the aged. Most of these disorders are associated with or caused by selective death of certain neuronal subpopulations. The mechanisms underlying the differential vulnerability of certain neuronal populations are still largely unexplored and few neuroprotective treatments are available to date. Elucidation of these mechanisms may lead to a greater understanding of the pathogenesis and treatment of neurodegenerative diseases. Moreover, preconditioning by a short seizure confers neuroprotection following a subsequent prolonged seizure. Our goal is to identify pathways that confer vulnerability and resistance to neurotoxic conditions by comparing the basal and preconditioned gene expression profiles of three differentially vulnerable hippocampal neuron populations. Hippocampal CA1 and CA3 pyramidal neurons are highly susceptible to seizures and ischemia, whereas dentate gyrus granule cells are relatively resistant. A brief preconditioning seizure confers protection to the pyramidal cells. We will first determine gene expression profiles of untreated rat CA1 and CA3 pyramidal cells, and dentate granule cells, using laser capture microscopy to obtain region-specific neuronal mRNA. We will then determine the effect of a brief preconditioning seizure, which is neuroprotective in CA1 and CA3, on these expression profiles. We hypothesize that common molecular mechanisms exist in neurons that determine their susceptibility to seizure-induced injury. Intrinsic differences in gene expression exist between hippocampal glutamatergic CA1 and CA3 pyramidal neurons, on the one hand, and dentate granule cells on the other, which contribute to the greater susceptibility of pyramidal neurons to degeneration in experimental stroke and epilepsy. We specifically hypothesize that differences in basal energy metabolism genes may confer differential susceptibility to neurodegeneration produced by seizures and ischemia. Anesthetized animals will be sacrificed by decapitation, and frozen 10 micron sections will be lightly stained with cresyl violet to identify cell layers in the hippocampus. Approximately 1000 neurons from each of the three cell layers will be isolated by LCM. Poly-A RNA will be amplified using a modified Eberwine protocol. The quality of our aRNA will be evaluated by quantitative RT-PCR of GluR6 and KA2 mRNA levels before we send the samples to the Center for labeling and hybridization to Affymetrix rat 230A arrays. We will provide a one-round amplification cDNA product to the center for labeling and hybridization. This protocol is identical to a previously approved study by Jim Greene in our laboratory.
2007-09-18 | E-GEOD-1994 | biostudies-arrayexpress
Project description:The present study aimed to use RNA sequencing to reveal the gene transcriptomic profile of PTZ-induced seizure rats and the difference of the PTZ model rat before and after treatment with Q808.
2022-03-01 | GSE193580 | GEO
Project description:The present study aimed to use RNA sequencing (RNA-seq) to reveal the gene transcriptomic profile of chronic PTZ-kindled seizure rats and the difference of the PTZ model rat before and after treatment with Q808.
2021-12-01 | GSE189785 | GEO
Project description:The GASH/Sal hamster (Genetic audiogenic seizure, Salamanca) is a model of audiogenic seizures with the epileptogenic focus localized in the inferior colliculus (IC). The sound-induced seizures exhibit a short latency (7-9 seconds), which implies innate protein disturbances in the IC as a basis for seizure susceptibility and generation. Here, we aim to study the protein profile in the GASH/Sal IC in comparison to controls. Protein samples from the IC were processed for enzymatic digestion and then analyzed by mass spectrometry in Data-Independent Acquisition mode. After identifying the proteins using the UniProt database, we selected those with differential expression. We identified 5254 proteins, of which 184 were differentially expressed, 126 upregulated and 58 downregulated. Moreover, a small number of proteins were uniquely found in the GASH/Sal or the control. The resuls indicated a protein profile alteration in the epileptogenic nucleus that might underlie the innate occuring audiogenic seizures in the GASH/Sal model.
2023-05-10 | PXD039755 | Pride
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