Abstract
Audiogenic epilepsy (AE), inherent to several rodent strains is widely studied as a model of generalized convulsive epilepsy. The molecular mechanisms that determine the manifestation of AE are not well understood. In the present work, we compared transcriptomes from the corpora quadrigemina in the midbrain zone, which are crucial for AE development, to identify genes associated with the AE phenotype. Three rat strains without sound exposure were compared: Krushinsky-Molodkina (KM) strain (100% AE-prone); Wistar outbred rat strain (non-AE prone) and “0” strain (partially AE-prone), selected from F2 KM × Wistar hybrids for their lack of AE. The findings showed that the KM strain gene expression profile exhibited a number of characteristics that differed from those of the Wistar and “0” strain profiles. In particular, the KM rats showed increased expression of a number of genes involved in the positive regulation of the MAPK signaling cascade and genes involved in the positive regulation of apoptotic processes. Another characteristic of the KM strain which differed from that of the Wistar and “0” rats was a multi-fold increase in the expression level of the Ttr gene and a significant decrease in the expression of the Msh3 gene. Decreased expression of a number of oxidative phosphorylation-related genes and a few other genes was also identified in the KM strain. Our data confirm the complex multigenic nature of AE inheritance in rodents. A comparison with data obtained from other independently selected AE-prone rodent strains suggests some common causes for the formation of the audiogenic phenotype.
Highlights
Epilepsy is one of most common neurological diseases and up to 30% of all epilepsy cases are characterized by high pharmacoresistance
As mentioned above, aiming to reveal the molecular mechanisms of Audiogenic epilepsy (AE), the gene expression profiles of KM rat corpora quadrigemina were compared with those of Wistar strain (W) rats, which do not exhibit AE, and “0” strain rats selected from KM × Wistar hybrids for the absence of AE phenotype (Figure 1A)
Analysis of the transcriptome in audiogenic rat strain (KM) and its comparison with the transcriptome of non-AE-prone rats in the original Wistar population and with “0” rats subjected to “reverse” selection allowed us to identify candidate genes for which expression changes are presumably the cause of AE phenotype acquisition. This approach met with certain difficulty, as some of the differences detected (1488 DEGs in the KM vs W rats and 494 DEGs in the KM vs “0” rats) may have been the result of changes in the genetic background of the strains, which was noted in both the KM and Wistar rats due to random changes occurring during the separate breeding of KM and W rat strains over many generations
Summary
Epilepsy is one of most common neurological diseases and up to 30% of all epilepsy cases are characterized by high pharmacoresistance. The partial or generalized seizures in these cases occur in response to sensory stimulation (tactile, optical or acoustical, or even as a reaction to the certain mood of a patient). These cases are rather rare (about 6%) and not well analyzed, and there are only sparse indications concerning their genetic base (Xue and Ritaccio, 2006; Maguire, 2012; Taylor et al, 2013; Dinopoulos et al, 2014; Dewhurst et al, 2015; SalaPadró et al, 2015; Atalar et al, 2020; Geenen et al, 2021). The data currently available generally support previously postulated hypotheses of polygenic inheritance of AE (Poletaeva et al, 2017), which is characteristic of many forms of human epilepsy (Koeleman, 2018; Leu et al, 2020)
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