Under What Circumstances Can Seizures Produce Hippocampal Injury: Evidence for Age-Specific Effects

Galanopoulou, Aristea S.; Vidaurre, Jorge; Moshé, Solomon L.

doi:10.1159/000069047

Cited by 23 publications

(19 citation statements)

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“…As susceptibility to seizure‐induced cell death can be modulated by the duration and severity of seizure induction (Berger et al 1986; Ferraro et al 1995; Galanopoulou et al 2002; Holmes 2002; Sucholmelova et al 2006), we also characterized congenic strains for seizure activity following kainate administration. Following kainate injection, we found a significant decrease in the latency to first seizure by anova in FVB.B6‐ Sicd2 mice ( n = 42) as compared to FVB‐like littermates ( n = 14; Fig.…”

Section: Resultsmentioning

confidence: 99%

Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death

Schauwecker¹

2010

Genes, Brain and Behavior

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Inbred strains of mice differ in their susceptibility to excitotoxin-induced cell death, but the genetic basis of individual variation is unknown. Prior studies with crosses of the FVB/NJ (seizure-induced cell death susceptible) mouse and the seizure-induced cell death resistant mouse, C57BL/6J, showed the presence of three quantitative trait loci (QTLs), named seizure-induced cell death 1 (Sicd1) to Sicd3. To better localize and characterize the Sicd2 locus, two reciprocal congenic mouse strains were created. While the B6.FVB-Sicd2 congenic mouse was without effect on modifying susceptibility to seizure-induced excitotoxic cell death, the FVB.B6-Sicd2 congenic mouse, in which the chromosome (Chr) 15 region of C57BL/6J was introgressed into FVB/NJ, showed reduced seizure-induced excitotoxic cell death following kainate administration. Phenotypic comparison between FVB and the congenic FVB.B6-Sicd2 strain confirmed that the Sicd2 interval harbors gene(s) conferring strong protection against seizureinduced excitotoxic cell death. Interval-specific congenic lines (ISCLs) that encompass Sicd2 on Chr 15 were generated and were used to fine-map this QTL. Resultant progeny were treated with kainate and examined for the extent of seizure-induced cell death in order to deduce the Sicd2 genotypes of the recombinants through linkage analysis. All of the ISCLs exhibited reduced cell death associated with the C57BL/6J phenotype; however, ISCL-2 showed the most dramatic reduction in seizure-induced cell death in both area CA3 and in the dentate hilus. These findings confirm the existence of polymorphic loci within the reduced critical region of Sicd2 that regulate the severity of seizure-induced cell death.

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Section: Resultsmentioning

confidence: 99%

Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death

Schauwecker¹

2010

Genes, Brain and Behavior

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“…Thus, our data confirm previous findings that the genetic background of mice significantly affects the susceptibility of hippocampal neurons to damage by pilocarpine (Borges et al, 2003; Müller et al, 2009a; Shibley and Smith, 2002; Winawer et al, 2007), and extends these findings to a comparison of a large number of inbred strains. As prior studies have suggested that differential susceptibility to seizure-induced cell death could result from a reduction in seizure activity (Berger et al, 1986; Ferraro et al, 1995; Galanopoulou et al, 2002; Holmes, 2002; Sucholmelova et al, 2006), we examined several seizure parameters. Irrespective of mouse strain examined, the latency to onset of status epilepticus or severity of seizure activity, as defined by the percentage of mice achieving stage 4/5 severe seizures, was not different.…”

Section: Discussionmentioning

confidence: 99%

Strain differences in seizure-induced cell death following pilocarpine-induced status epilepticus

Schauwecker¹

2012

Neurobiology of Disease

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Mouse strains differ from one another in their susceptibility to seizure-induced excitotoxic cell death. Previously, we have demonstrated that mature inbred strains of mice show remarkable genetic differences in susceptibility to the neuropathological consequences of seizures in the kainate model of status epilepticus. At present, while the cellular mechanisms underlying strain-dependent differences in susceptibility remain unclear, some of this variation is assumed to have a genetic basis. However, it remains unclear whether strain differences in susceptibility to seizure-induced cell death observed following kainate administration are observed following systemic administration of other chemoconvulsants. In rodents, the cholinomimetic convulsant pilocarpine is widely used to induce status epilepticus (SE), followed by hippocampal damage and spontaneous recurrent seizures, resembling temporal lobe epilepsy. This model has initially been described in rats, but is increasingly used in mice. We characterized neuronal pathologies after pilocarpine-induced status epilepticus (SE) in eight inbred strains of mice focusing on the hippocampus. A ramping-up dose protocol for pilocarpine was used and behavior was monitored for 4–5 hours. While we did not observe any significant differences in seizure latency or duration to pilocarpine among the inbred strains, we did observe a significant difference in susceptibility to the neuropathological consequences of pilocarpine-induced SE. Of the eight genetically diverse mouse strains screened for pilocarpine-induced status, BALB/cJ and BALB/cByJ were the only two strains that were resistant to the neuropathological consequences of seizure-induced cell death. Additional studies of these murine strains may be useful for investigating genetic influences on pilocarpine-induced status epilepticus.

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“…The early periods of life, when brain development is still incomplete, susceptibility to seizures is increased [3, 4]. However, a combination of biological factors (genetic, age-related processes, epigenetic or environmental factors) protect neurons from seizure-induced injury, epileptogenesis, or mortality to a greater extent than the adult brain is protected [5]. It is increasingly recognized that seizures may leave their imprint on the developing brain by altering the way that neurons differentiate, connect, and communicate to each other, even if, in many cases, such changes may be ultimately compensated for.…”

Section: Introductionmentioning

confidence: 99%

Altered GABA Signaling in Early Life Epilepsies

Briggs

Galanopoulou

2011

Neural Plasticity

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The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAA signaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAA receptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAA signaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain.

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Under What Circumstances Can Seizures Produce Hippocampal Injury: Evidence for Age-Specific Effects

Cited by 23 publications

References 103 publications

Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death

Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death

Strain differences in seizure-induced cell death following pilocarpine-induced status epilepticus

Altered GABA Signaling in Early Life Epilepsies

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