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MEST in control mice and chromosome 5 congenic mice on a D2 genetic background. Top of each bar represents the mean (SD) MEST expressed in milliamperes. The number in parentheses above each bar indicates the number of mice tested. *P 0.05; **P 0.01 vs. D/D mice of same sex (ANOVA, Newman-Keuls). Strain designations: D/D, control D2 background; D.B-Szs11, D2.B6-Szs11 (see MATERIALS AND METHODS).
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Multiple quantitative trait locus (QTL) mapping studies designed to localize seizure susceptibility genes in C57BL/6 (B6, seizure resistant) and DBA/2 (D2, seizure susceptible) mice have detected a significant effect originating from midchromosome 5. To confirm the presence and refine the position of the chromosome 5 QTL for maximal electroshock se...
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... testing data for the D2.B6-Szs11 congenic strain are depicted in Fig. 3. Two-way ANOVA documents statistically significant effects of strain (P 1 10 8 , F 74.28) and sex (P 1 10 5 , F 23.8), as well as a statistically significant interaction effect (P 0.03, F 5.0). Post hoc analysis documents significantly higher MEST (means SD) in con- genic mice of both sexes compared with control (congenic males: 29.7 2.8 mA, control males: 25.3 2.3 mA; congenic females: 28.0 3.2, control females: 21.1 1.3). Between-group P values and numbers of mice tested are shown in Fig. ...
Context 2
... testing data for the D2.B6-Szs11 congenic strain are depicted in Fig. 3. Two-way ANOVA documents statistically significant effects of strain (P 1 10 8 , F 74.28) and sex (P 1 10 5 , F 23.8), as well as a statistically significant interaction effect (P 0.03, F 5.0). Post hoc analysis documents significantly higher MEST (means SD) in con- genic mice of both sexes compared with control (congenic males: 29.7 2.8 mA, control males: 25.3 2.3 mA; congenic females: 28.0 3.2, control females: 21.1 1.3). Between-group P values and numbers of mice tested are shown in Fig. ...
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... As well, a number of studies have indicated that there are substantial differences in seizure susceptibility induced by electrical or chemical means in different strains that are genetically determined [21,25,[61][62][63][64]. In particular, it has been reported that seizure susceptibility is a polygenetic phenomenon with loci of significant effect on chromosomes 1, 5, 7 and 15 [61,63,[65][66]. Together, this suggests that a discrepancy between seizure sensitivity and seizure-induced cell death is likely due to activation of different mechanisms and/or different genes related to increased excitability versus those that protect neurons. ...
Seizure-induced cell death is believed to be regulated by multiple genetic components in addition to numerous external factors. We previously defined quantitative trait loci that control susceptibility to seizure-induced cell death in FVB/NJ (susceptible) and C57BL/6J (resistant) mice. Two of these quantitative trait loci assigned to chromosomes 18 (Sicd1) and 15 (Sicd2), control seizure-induced cell death resistance. In this study, through the use of a series of novel congenic strains containing the Sicd1 and Sicd2 congenic strains and different combinations of the Sicd1 or Sicd2 sub region(s), respectively, we defined these genetic interactions. We generated a double congenic strain, which contains the two C57BL/6J differential segments from chromosome 18 and 15, to determine how these two segments interact with one another. Phenotypic comparison between FVB-like littermates and the double congenic FVB.B6-Sicd1/Sicd2 strain identified an additive effect with respect to resistance to seizure-induced excitotoxic cell death. It thus appears that C57BL/6J alleles located on chromosomes 18 and 15 interact epistatically in an additive manner to control the extent of seizure-induced excitotoxic cell death. Three interval-specific congenic lines were developed, in which either segments of C57BL/6J Chr 18 or C57BL/6J Chr 15 were introduced in the FVB/NJ genetic background, and progeny were treated with kainate and examined for the extent of seizure-induced cell death. All of the interval-specific congenic lines exhibited reduced cell death in both area CA3 and the dentate hilus, associated with the C57BL/6J phenotype. These experiments demonstrate functional interactions between Sicd1 and Sicd2 that improve resistance to seizure-induced excitotoxic cell death, validating the critical role played by gene-gene interactions in excitotoxic cell death.
... QTL responsible for strain differences in susceptibility to seizures induced by chemoconvulsants, electroshock and handling have been mapped in mice. Several previous studies mapped QTL responsible for susceptibility to induced seizures to chromosome 5 in regions overlapping the Dsm1 and Dsm4 loci (Ferraro et al 1997;Ferraro et al 1999;Ferraro et al 2001;Ferraro et al 2007). The Bis4 QTL influencing susceptibility to seizures induced by β-carboline was mapped to chromosome 7 in a region that overlaps the Dsm2 interval (Gershenfeld et al. 1999). ...
Epilepsy is a common neurological disorder affecting approximately 1% of the population. Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes. More than 800 mutations in the voltage-gated sodium channel SCN1A have been reported in patients with generalized epilepsy with febrile seizures plus and Dravet syndrome. Heterozygous loss-of-function mutations in SCN1A result in Dravet syndrome, a severe infant-onset epileptic encephalopathy characterized by intractable seizures, developmental delays and increased mortality. A common feature of monogenic epilepsies is variable expressivity among individuals with the same mutation, suggesting that genetic modifiers may influence clinical severity. Mice with heterozygous deletion of Scn1a (Scn1a(+/-) ) model a number of Dravet syndrome features, including spontaneous seizures and premature lethality. Phenotype severity in Scn1a(+/-) mice is strongly dependent on strain background. On the 129S6/SvEvTac strain Scn1a(+/-) mice exhibit no overt phenotype, while on the (C57BL/6J x 129S6/SvEvTac)F1 strain Scn1a(+/-) mice exhibit spontaneous seizures and early lethality. To systematically identify loci that influence premature lethality in Scn1a(+/-) mice, we performed genome scans on reciprocal backcrosses. QTL mapping revealed modifier loci on mouse chromosomes 5, 7, 8 and 11. RNA-seq analysis of strain-dependent gene expression, regulation and coding sequence variation provided a list of potential functional candidate genes at each locus. Identification of modifier genes that influence survival in Scn1a(+/-) mice will improve our understanding of the pathophysiology of Dravet syndrome and may suggest novel therapeutic strategies for improved treatment of human patients.
... Testing specific congenic strains in which potential genes of interest will be introduced will help define the importance of the QTLs detected in this study. This approach has been successful in other genetic studies [23,24]. Generation of bacterial artificial chromosome (BAC) transgenic mice using the candidate genes we have identified will also be beneficial in evaluating the importance of our novel QTLs. ...
Blood--brain barrier (BBB) disruption is an integral feature of numerous neurological disorders. However, there is a relative lack of knowledge regarding the underlying molecular mechanisms of immune-mediated BBB disruption. We have previously shown that CD8 T cells and perforin play critical roles in initiating altered permeability of the BBB in the peptide-induced fatal syndrome (PIFS) model developed by our laboratory. Additionally, despite having indistinguishable CD8 T cell responses, C57BL/6J (B6) mice are highly susceptible to PIFS, exhibiting functional motor deficits, increased astrocyte activation, and severe CNS vascular permeability, while 129S1/SvImJ (129S1) mice remain resistant. Therefore, to investigate the potential role of genetic factors, we performed a comprehensive genetic analysis of (B6 x 129S1) F2 progeny to define quantitative trait loci (QTL) linked to the phenotypic characteristics stated above that mediate CD8 T cell-initiated BBB disruption.
Using single nucleotide polymorphism (SNP) markers and a 95% confidence interval, we identified one QTL (PIFS1) on chromosome 12 linked to deficits in motor function (SNP markers rs6292954, rs13481303, rs3655057, and rs13481324, LOD score = 3.3). In addition we identified a second QTL (PIFS2) on chromosome 17 linked to changes in CNS vascular permeability (SNP markers rs6196216 and rs3672065, LOD score = 3.7).
The QTL critical intervals discovered have allowed for compilation of a list of candidate genes implicated in regulating functional deficit and CNS vascular permeability. These genes encode for factors that may be potential targets for therapeutic approaches to treat disorders characterized by CD8 T cell-mediated BBB disruption.
... In situ expression data from the Allen Brain Atlas (ABA, www.brain-map.org), as well as other expression and immunohistochemical studies, demonstrate that Kcnj9/Kir3.3 is expressed strongly in neurons throughout the brain, including in the hippocampus, cerebellum, and brainstem [48,49,50]. Variation in Kcnj9 expression has been strongly implicated in barbiturate withdrawal in mice [51,52], and possibly in seizure sensitivity [45,53]. On the other hand, Kcnj10/Kir4.1 is expressed diffusely in glial cells [54,55,56]. ...
Fluid licking in mice is a rhythmic behavior that is controlled by a central pattern generator (CPG) located in a complex of brainstem nuclei. C57BL/6J (B6) and DBA/2J (D2) strains differ significantly in water-restricted licking, with a highly heritable difference in rates (h(2)≥0.62) and a corresponding 20% difference in interlick interval (mean ± SEM = 116.3±1 vs 95.4±1.1 ms). We systematically quantified motor output in these strains, their F(1) hybrids, and a set of 64 BXD progeny strains. The mean primary interlick interval (MPI) varied continuously among progeny strains. We detected a significant quantitative trait locus (QTL) for a CPG controlling lick rate on Chr 1 (Lick1), and a suggestive locus on Chr 10 (Lick10). Linkage was verified by testing of B6.D2-1D congenic stock in which a segment of Chr 1 of the D2 strain was introgressed onto the B6 parent. The Lick1 interval on distal Chr 1 contains several strong candidate genes. One of these is a sodium/potassium pump subunit (Atp1a2) with widespread expression in astrocytes, as well as in a restricted population of neurons. Both this subunit and the entire Na(+)/K(+)-ATPase molecule have been implicated in rhythmogenesis for respiration and locomotion. Sequence variants in or near Apt1a2 strongly modulate expression of the cognate mRNA in multiple brain regions. This gene region has recently been sequenced exhaustively and we have cataloged over 300 non-coding and synonymous mutations segregating among BXD strains, one or more of which is likely to contribute to differences in central pattern generator tempo.
... Genes that influence a mutant phenotype can be identified systematically by evaluating the seizure phenotype on different background strains. Several strain-dependent seizure susceptibility loci and genes have been identified (Chaix et al. 2007; Ferraro et al. 2001 Ferraro et al. , 2004 Ferraro et al. , 2007a Ferraro et al. , 2007b Ferraro et al. , 2010b Ferraro et al. , 2011 Frankel et al. 1995; Gershenfeld et al. 1999; Maihara et al. 2000; Winawer et al. 2011). The transgenic mouse model Scn2a Q54 has an epilepsy phenotype due to a mutation in Scn2a that slows channel inactivation and results in persistent sodium current (Kearney et al. 2001). ...
Epilepsy is a neurological disorder affecting approximately 1% of the worldwide population. Mutations in voltage-gated sodium channels have been identified in several monogenic epilepsy syndromes. Over 800 mutations have been identified in the voltage-gated sodium channel genes SCN1A and SCN2A in human epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In GEFS+ families, affected members with the same mutation often display variability in clinical severity of the disease. This suggests that additional genes modify the effect of the primary mutation, resulting in the variable clinical presentation. The Scn2a(Q54) transgenic mouse model has an epilepsy phenotype that varies depending on the genetic strain background. Scn2a(Q54) mice congenic on the C57BL/6J strain exhibit delayed seizure onset and improved survival compared to (C57BL/6J × SJL/J)F1.Q54 mice. Two modifier loci of Scn2a(Q54) seizure susceptibility were mapped and designated Moe1 (modifier of epilepsy) on chromosome (chr) 11 and Moe2 on chr 19. To confirm Moe1 and refine its position, we generated interval-specific congenic lines carrying C57BL/6J-derived chr 11 alleles on the SJL/J strain and refined the map position to 89-104 Mb. We then used RNA-Seq for candidate analysis in the modifier region. C57BL/6J and SJL/J male and female brain RNAs were sequenced, revealing numerous significant transcriptome differences and coding single-nucleotide polymorphisms. Additional consideration of gene function and expression suggested several strong candidate modifier genes, including two voltage-gated calcium channel subunits, Cacna1g and Cacnb1, and the proline and acidic amino acid-rich basic leucine zipper transcription factor, Hlf.
... It has previously been established that genetic background can considerably affect the seizure thresholds of mice. Loci responsible for strain differences in susceptibility to seizures, triggered by chemoconvulsants, such as kainic acid, or non-pharmacological manipulations, have been mapped to specific mouse chromosomes ( Ferraro et al., 1997Ferraro et al., , 2001Ferraro et al., , 2004Ferraro et al., , 2007aFerraro et al., ,b, 2010Ferraro et al., , 2011Todorova et al., 2006). The identified genomic loci map to chromosomes 1, 2, 4, 5, 7, 10, 11, 12, 15 and 18 with the highest density on chromosomes 1, 5, 7, and 10 where loci from several different crosses coincide. ...
Growing evidence has indicated that genetic factors contribute to the etiology of seizure disorders. Most epilepsies are multifactorial, involving a combination of additive and epistatic genetic variables. However, the genetic factors underlying epilepsy have remained unclear, partially due to epilepsy being a clinically and genetically heterogeneous syndrome. Similar to the human situation, genetic background also plays an important role in modulating both seizure susceptibility and its neuropathological consequences in animal models of epilepsy, which has too often been ignored or not been paid enough attention to in published studies. Genetic homogeneity within inbred strains and their general amenability to genetic manipulation have made them an ideal resource for dissecting the physiological function(s) of individual genes. However, the inbreeding that makes inbred mice so useful also results in genetic divergence between them. This genetic divergence is often unaccounted for but may be a confounding factor when comparing studies that have utilized distinct inbred strains. The purpose of this review is to discuss the effects of genetic background strain on epilepsy phenotypes of mice, to remind researchers that the background genetics of a knockout strain can have a profound influence on any observed phenotype, and outline the means by which to overcome potential genetic background effects in experimental models of epilepsy.
... Comparison of seizure thresholds between congenic strain and that one which contain the parental genetic background genes indicated that mice from strains having chromosome 5 alleles from D2 and B6 genetic background exhibited significantly lower thresholds, than control littermates, and v.v. -congenic mice harboring B6 chromosome 5 alleles on a D2 genetic background exhibit significantly higher thresholds (Ferraro et al., 2007). Thus that was another chromosome locus which could be also responsible for AE proneness differences between DBA/2J and C57BL/6J mice. ...
... Typically, rodents are used to conduct these epilepsy studies and the type of rodent strain used seems crucial. Studies in inbred murine strains in particular, have yielded considerable information regarding genetic influences on both seizure susceptibility and its neuropathological consequences (Ferraro et al., 2004Ferraro et al., , 2007 Kong et al., 2008; Mazarati et al., 2004; Schauwecker, 2010; Weinshenker et al., 2001). Previously, we demonstrated that administration of the chemoconvulsant, kainic acid, results in significantly different extents of hippocampal neurodegeneration among inbred mouse strains (Schauwecker and Steward, 1997). ...
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 h. 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.
... It would not be at all surprising that this Chr1 locus plays a role in ASP. In addition, there is a significant locus effect on Chr5 influencing the difference in seizure susceptibility between B6 and D2 mice [18]. Other regions affecting ASP in other strains of mice have identified loci on Chr13 [19] and Chr10 [20]. ...
Juvenile mice of the DBA/2J strain undergo generalised seizures when exposed to a high-intensity auditory stimulus. Genetic analysis identified three different loci underlying this audiogenic seizure proneness (ASP)-Asp1, Asp2 and Asp3 on chromosomes 12, 4 and 7, respectively. Asp1 is thought to have the strongest influence, and mice with only Asp1 derived from the DBA/2J strain are reported to exhibit ASP. The aim of this study was to characterise more accurately the contributions of the Asp1 and Asp3 loci in ASP using congenic strains. Each congenic strain contains a DBA/2J-derived interval encompassing either Asp1 or Asp3 on a C57BL/6J genetic background. A double congenic C57BL/6J strain containing both Asp loci derived from DBA/2J was also generated. Here, we report that DBA/2J alleles at both of these Asp loci are required to confer ASP because congenic C57BL/6 mice harbouring DBA/2J alleles at only Asp1 or Asp3 do not exhibit ASP, whereas DBA/2J alleles at both loci resulted in increased susceptibility for audiogenic seizure in double congenic C57BL/6 mice.
... Previous work from our laboratory using a genetic model involving B6 and D2 mice identified MEST QTLs on chromosomes 1, 2, 5 and 15 (Ferraro et al. 2001(Ferraro et al. , 2007a(Ferraro et al. ,b, 2010. Given the genetic interrelationship between B6, B10S, BKS and D2 mice, the lack of correspondence between the locations of major QTLs in the two studies is unexpected, although not unprecedented, as previous work has documented similar results in other strain combinations (Frankel et al. 1994). ...
... BKS mice exhibited D2 alleles more prominently in the previously mapped QTL intervals on chromosomes 5 and 15 and weak evidence for linkage of MEST to markers on both chromosomes was obtained in the present study. The 95% credible interval for the chromosome 5 QTL (Fig. 2) overlaps with the congenic interval used to refine the map position of a chromosome 5 QTL in B6 and D2 mice (Ferraro et al. 2007a). Two chromosome 15 loci were also detected as having weak effects in the initial contingency analysis (Table 2) and these are found at positions consistent with initial mapping (Ferraro et al. 2001) and more recent fine mapping of a chromosome 15 MEST QTL in B6 and D2 strains (Ferraro et al. 2010). ...
We mapped the quantitative trait loci (QTL) that contribute to the robust difference in maximal electroshock seizure threshold (MEST) between C57BLKS/J (BKS) and C57BL10S/J (B10S) mice. BKS, B10S, BKS × B10S F1 and BKS × B10S F2 intercross mice were tested for MEST at 8-9 weeks of age. Results of F2 testing showed that, in this cross, MEST is a continuously distributed trait determined by polygenic inheritance. Mice from the extremes of the trait distribution were genotyped using microarray technology. MEST correlated significantly with body weight and sex; however, because of the high correlation between these factors, the QTL mapping was conditioned on sex alone. A sequential series of statistical analyses was used to map QTLs including single-point, multipoint and multilocus methods. Two QTLs reached genome-wide levels of significance based upon an empirically determined permutation threshold: chromosome 6 (LOD = 6.0 at ∼69 cM) and chromosome 8 (LOD = 5.7 at ∼27 cM). Two additional QTLs were retained in a multilocus regression model: chromosome 3 (LOD = 2.1 at ∼68 cM) and chromosome 5 (LOD = 2.7 at ∼73 cM). Together the four QTLs explain one third of the total phenotypic variance in the mapping population. Lack of overlap between the major MEST QTLs mapped here in BKS and B10S mice and those mapped previously in C57BL/6J and DBA/2J mice (strains that are closely related to BKS and B10S) suggest that BKS and B10S represent a new polygenic mouse model for investigating susceptibility to seizures.
