Experiment
In the current study, using reciprocal congenic strains B6.D2-Szs1 and D2.B6-Szs1 a comprehensive evaluation of the impact of allelic variation(s) within the QTL Szs1 on the inherited occurrence of the generalized non-convulsive spontaneous SWDs (spike and waves discharges) of D2 was carried out. A striking feature of the DBA/2J (D2) strain, not present in C57BL/6J (B6), is the frequent occurrence of high-amplitude, 6-8 hertz SWDs, which represents an endophenotype of thalamo-cortically generated SWDs typical of absence seizures, one of the most common forms of idiopathic generalized epilepsy (IGE). In all models of absence seizure, SWDs in D2 mice are associated with behavioral arrest.
Adult mice, 10-4 weeks of age, from each reciprocal congenic strain containing the Szs1 QTL, D2.B6-(D1Mit390-D1Mit17) and B6.D2-(D1Mit30-D1Mit17), were surgically prepared for EEG monitoring. EEG traces were analyzed by performing power spectrum with a fast Fourier algorithm using custom software written in Igor. Characteristics of SWD (duration, frequency and occurrence) were compared between strains using Mann-Whitney U test.
The results showed that congenic manipulation of the Szs1 locus drastically reduced the number and the duration of SWDs in D2.B6-Szs1 mice, however, it failed to induce the full expression of SWDs in B6.D2-Szs1. The results demonstrated that the occurrence of SWDs in D2 animals is under a polygenic control and therefore, the coupled D2 and B6 strains might be a useful model to dissect the genetic determinants of polygenic SWDs characteristic of typical absence seizures.
High resolution mapping of Szs1 showed that out of 120 genes in the introgressed congenic interval, 12 genes satisfy both criteria of being expressed in the brain and having a missense single nucleotide polymorphism (SNP). Among this latter group, one encodes a protein involved directly in the transport of ions across cell membranes: Kcnj10. This gene encodes an inward-rectifier potassium ion channel Kir4.1 predominantly expressed by glial cells. Homozygous Kcnj10 knockout mice show a severe demyelinating syndrome associated with multiple neurological defects including seizures and short life span.
The authors propose that changes in genes within or regulated by Szs1 such as Kcnj10 or Cacna1g, might account for the drastic decrease on SWDs occurrence in D2.B6-Szs1 mice when compared to D2 mice.
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