A quantitative trait locus on chromosome 18 is a critical determinant of excitotoxic cell death susceptibility

Abstract

C57BL/6J (B6) and FVB/NJ (FVB) mice are phenotypically distinct in their susceptibility to seizure-induced cell death after kainate administration. Previous studies using quantitative trait loci (QTLs) mapping established that the distal region of mouse chromosome 18 contains a gene(s) that is probably responsible for the difference in seizure-induced cell death susceptibility between two inbred strains, B6 and FVB, that are relatively resistant and susceptible, respectively, to seizure-induced cell death. The genetic locus has been mapped to a approximately 12-centimorgan region of chromosome 18, designated as seizure-induced cell death 1 (Sicd1). In order to confirm the Sicd1 QTL, we have developed congenic mouse strains containing the relevant donor segment from the resistant B6 strain on the susceptible FVB background, also referred to as the FVB.B6-Sicd1 congenic strain. Congenic and FVB littermate controls were tested in a seizure-induced cell death paradigm. The presence of B6 chromosome 18 alleles on an FVB genetic background conferred protection against seizure-induced cell death, as compared with FVB littermate controls. To further localize the Sicd1 QTL, new congenic lines carrying overlapping intervals of the B6 segment were created [interval-specific congenic lines (ISCLs)-1-4] and assessed for seizure-induced cell death phenotype. All of the ISCLs exhibited reduced cell death associated with the B6 phenotype, as compared with the parental FVB strain. The most dramatic of these, ISCL-4, showed a nearly four-fold reduction in the extent of seizure-induced cell death. This suggests that ISCL-4 contains the putative gene(s) of the Sicd1 QTL.

Galanin Receptor 1 Deletion Exacerbates Hippocampal Neuronal Loss after Systemic Kainate Administration in Mice

“…These findings suggest that host genetic factors confer protection against hippocampal damage following seizures in resistant strains. Using these mice, we previously identified and confirmed three significant QTL on chromosome 18, 15, and 4 in the mouse genome, responsible for seizure-induced cell death susceptibility through the creation of reciprocal congenic strains and interval-specific congenic lines of mice [19], [20]. The strongest and most significant QTL that determines susceptibility is located on Chr 18 and previous studies have identified galanin receptor type 1 (GalR1) as a compelling candidate gene for the locus on Chr 18 based on expression analyses [21] and its known role as a neuroprotective factor for the hippocampus.…”

“…Quantitative analysis of hippocampal cell loss was performed in a blinded manned on cresyl violet-stained sections according to previously established protocols [17], [19], [20]. The number of Nissl-stained neuronal profile in areas CA3, CA1, the dentate hilus, and the dentate gyrus were counted in both the right and left hippocampus in horizontal sections for each animal by using four to five Nissl-stained sections that were ∼240 µm apart at the level of the ventral hippocampus.…”

The relevance of individual genetic background and its role in animal models of epilepsy

“…Therefore, hippocampal cell death after seizures and the related molecular mechanisms might not be a general phenomenon, but depend on a complicated interaction between the genetic background and the protocol of seizure induction. Furthermore, while little is known about the distinct factors that cause strain differences in hippocampal vulnerability following seizure induction, modifying genes and quantitative trait loci (QTL) are now recognized as exerting a major influence on regulating the susceptibility to seizure-induced cell death (Kong et al, 2008; Lorenzana et al, 2007; Schauwecker et al, 2004; Schauwecker, 2011). Nevertheless, the genetic basis of variation in seizure-induced cell death remains unclear.…”

Kainic Acid-Induced Neuronal Degeneration in Hippocampal Pyramidal Neurons Is Driven by Both Intrinsic and Extrinsic Factors: Analysis of FVB/N↔C57BL/6 Chimeras

“…First, Schauwecker and colleagues (Schauwecker et al, 2004) found a distal region on chromosome 18, that includes the GalR1 locus, houses a quantitative trait locus that significantly influences susceptibility to kainic acid-induced cell death (called,Sicd1). This region was further refined using FVB.B6-Sicd1 lines of mice and the GalR1 locus remained with the region (Lorenzana et al, 2007). Second, recent evidence has demonstrated that GalR1 mRNA is differentially expressed in the hippocampus of sensitive (FVB) and resistant (B6) strains under baseline conditions (Kong et al, 2008;Schauwecker, 2010a).…”