Genetic control of sensitivity to hippocampal cell death induced by kainic acid: A quantitative trait loci analysis

Schauwecker, Paula Elyse; Williams, Robert W.; Santos, Julia Belen

doi:10.1002/cne.20245

Cited by 43 publications

(100 citation statements)

References 65 publications

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“…Using the CSS A/J × B6 panel, we have found evidence on mouse Chromosomes 10 and 18 of QTLs contributing to seizure susceptibility. Two prior seizure-related overlapping QTLs have been reported on Chromosome 18 for susceptibility to kainic acid-induced hippocampal cell death and limbic seizures (Ferraro et al 1997;Schauwecker et al 2004) in C57Bl/6 × FVB/N and C57Bl/6 × DBA/2J crosses (Schauwecker et al 2004). Identification of a QTL for multiple different seizure and/or cell death susceptibility phenotypes (and for kainic acid pilocarpine) could suggest shared genetic contributions to these different limbic outcomes and give insight into pathophysiology.…”

Section: Discussionmentioning

confidence: 98%

“…C57BL/6J (B6) mice have been shown to be resistant to seizures; the A/J strain has been less studied but appears more susceptible to seizures. There is also evidence for strain-specific susceptibility to seizure-induced hippocampal damage (Chen et Schauwecker et al 2004). QTL mapping has also identified modifier loci that determine the severity of the epilepsy phenotype related to mutations in voltage-gated sodium channels (Bergren et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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Use of chromosome substitution strains to identify seizure susceptibility loci in mice

et al. 2007

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Seizure susceptibility varies among inbred mouse strains. Chromosome substitution strains (CSS), in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing, may be used to identify quantitative trait loci (QTLs) that contribute to seizure susceptibility. QTLs for susceptibility to pilocarpine-induced seizures, a model of temporal lobe epilepsy, have not been reported, and CSS have not previously been used to localize seizure susceptibility genes. We report QTLs identified using a B6 (host) × A/J (donor) CSS panel to localize genes involved in susceptibility to pilocarpine-induced seizures. Three hundred fifty-five adult male CSS mice, 58 B6, and 39 A/J were tested for susceptibility to pilocarpine-induced seizures. Highest stage reached and latency to each stage were recorded for all mice. B6 mice were resistant to seizures and slower to reach stages compared to A/J mice. The CSS for Chromosomes 10 and 18 progressed to the most severe stages, diverging dramatically from the B6 phenotype. Latencies to stages were also significantly shorter for CSS10 and CSS18 mice. CSS mapping suggests seizure susceptibility loci on mouse Chromosomes 10 and 18. This approach provides a framework for identifying potentially novel homologous candidate genes for human temporal lobe epilepsy.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

et al. 2007

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“…In order to evaluate the severity of KA-induced excitotoxic brain damage in different strains of mice, brains from each strain of mice were processed for light microscopic histopathologic evaluation according to previously published methods (Schauwecker et al, 2004). Briefly, seven days after seizure induction by KA, mice were anesthetized with Avertin and transcardially perfused with 4% paraformaldehyde in 0.1M phosphate buffer (pH 7.4).…”

Section: Histological Stainingmentioning

confidence: 99%

Effect of age on kainate-induced seizure severity and cell death

et al. 2008

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While the onset and extent of epilepsy increases in the aged population, the reasons for this increased incidence remain unexplored. The present study used two inbred strains of mice (C57BL/6J and FVB/NJ) to address the genetic control of age-dependent neurodegeneration by building upon previous experiments that have identified phenotypic differences in susceptibility to hippocampal seizure-induced cell death. We determined if seizure induction and seizure-induced cell death are affected differentially in young adult, mature, and aged male C57BL/6J and FVB/NJ mice administered the excitotoxin, kainic acid. Dose response testing was performed in three-four groups of male mice from each strain. Following kainate injections, mice were scored for seizure activity and brains from mice in each age group were processed for light microscopic histopathologic evaluation seven days following kainate administration to evaluate the severity of seizure-induced brain damage. Irrespective of the dose of kainate administered or the age group examined, resistant strains of mice (C57BL/6J) continued to be resistant to seizure-induced cell death. In contrast, aged animals of the FVB/NJ strain were more vulnerable to the induction of behavioral seizures and associated neuropathology after systemic injection of kainic acid than young or middle-aged mice.Results from these studies suggest that the age-related increased susceptibility to the neurotoxic effects of seizure induction and seizure-induced injury is regulated in a strain-dependent manner, similar to previous observations in young adult mice. Keywords mouse strain; excitotoxicity; kainic acid; epilepsy; cell death; aging Knowledge about the influence of aging on the susceptibility of the brain to seizure disorders is of critical importance in geriatric medicine and public health. Epilepsy is the most common neurological disorder after stroke, affecting more than 50 million persons worldwide and with a 2-3% life time risk of being given a diagnosis of epilepsy (Browne and Holmes, 2001). Currently it is well known that there is a significant incidence of epilepsy in children. However, less clearly recognized but of increasing importance is the significant incidence of epilepsy in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the elderly population. Recent studies in the United States and Europe indicate that the agespecific incidence of epilepsy is higher in those over the age of 65 years than in those in the first decade of life (Talli...

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“…We tested 91 SSLP primer pairs from the database for polymorphism between BALB/cJ and SJL/J mice and used 65 that produced PCR fragments differing in lengths between strains by at least 2 and 8 nucleotides for automated and manual analysis, respectively. We prepared DNA from tail snips of the backcross mice (30). We obtained 12,373 genotypes of a total possible 12,480 (99.14%).…”

Section: Qtl Analysis For Identification Of Mav-1 Susceptibility Genementioning

confidence: 99%

Identification of Quantitative Trait Loci for Susceptibility to Mouse Adenovirus Type 1

Welton

Chesler

Sturkie

et al. 2005

J Virol

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Adenoviruses cause 5 to 10% of respiratory illnesses in children and are associated with acute pneumonia in children in developing countries, where the viruses are a major cause of illness and death (21). Five to 15% of pediatric bone marrow transplant patients develop adenovirus infections; morbidity ranges from 50 to 80% (8,9,12,16,27,38). However, very little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease because it can be studied in the natural host.Inbred strains of mice with different susceptibilities to MAV-1 infection have been identified previously (14,33). SJL/J mice are highly susceptible to MAV-1 infection, with a 50% lethal dose (LD 50 ) more than 4 log units lower than those for other strains of mice, including C3H/HeJ, BALB/cJ, 129/J, and C57BL/6J (33). In vivo studies with immunodeficient mice have demonstrated the importance of innate and adaptive immunity in response to MAV-1 infections. The presence of T cells contributes to immunopathology during the acute phase of infection and to clearance of virus in long-term infection (25). B cell-deficient mice are highly susceptible to MAV-1 infections and die very early, at 6 to 9 days postinfection (p.i.), of a disseminated infection (26). T cell-independent production of neutralizing antiviral immunoglobulin M is a critical factor for control of MAV-1 infection. Infection of primary cells of susceptible and resistant mice ex vivo gives equivalent yields of virus, and sublethal irradiation renders resistant mice susceptible (33). These results suggest that host immune response factors play a role in susceptibility to MAV-1.We have compared the adaptive immune responses that have been characterized as being important for control of MAV-1 infection (25, 26), as well as NK cell function and induction of cytokines and chemokines by infection, in susceptible and resistant mice (A. Welton and K. Spindler, unpublished data). To date, we have not identified physiological differences between susceptible and resistant strains have been identified by using these approaches. In this report, we show that MAV-1 susceptibility is linked to mouse chromosome 15 (Chr 15) and unlinked to the H-2 major histocompatibility locus. We used a genomewide search strategy, quantitative trait locus (QTL) detection, to identify host factors associated with susceptibility to MAV-1. This method is advantageous because it does not require prior hypotheses of the pathogenic mechanism and can therefore reveal novel pathways. We measured the susceptibility phenotypes of 192 backcross progeny. The analysis identified a major QTL on distal Chr 15 with a highly significant logarithm of odds (LOD) score of 21.2 and a minor QTL on Chr 5 with a suggestive LOD score of 1.2, based on 5,000 permutations of the mapping analysis. A LOD score of 21 means that the odds are 10 21 :1 in favor of linkage. The Chr 15 locus alone accou...

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Genetic control of sensitivity to hippocampal cell death induced by kainic acid: A quantitative trait loci analysis

Cited by 43 publications

References 65 publications

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

Effect of age on kainate-induced seizure severity and cell death

Identification of Quantitative Trait Loci for Susceptibility to Mouse Adenovirus Type 1

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