Transcriptome of the Krushinsky-Molodkina Audiogenic Rat Strain and Identification of Possible Audiogenic Epilepsy-Associated Genes

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.

Rodent Models of Audiogenic Epilepsy: Genetic Aspects, Advantages, Current Problems and Perspectives

“…A direct cause of these types of epilepsy could lie, particularly, in changes of signaling cascades activity, including those regulating neurotransmitter release and ion channel gene expression (e.g., MAPK and mTOR) [ 10 , 57 , 117 , 118 , 119 , 120 ]. The imbalance in signaling cascades activity can lead, also, to cell cycle deteriorations during neuronal proliferation; the development of mitochondriopathy; excessive apoptosis, affecting definite types of neurons; the development of neuroinflammation; and other mechanisms of epileptogenesis, which has been mainly studied in animal models [ 121 , 122 , 123 , 124 , 125 , 126 ]. Thus, some cases of genetically determined epilepsy are the result of disturbances in the complex networks regulating the development and homeostasis of the nervous system.…”

“…A certain percentage of these animals developed epileptiform seizures in response to loud sounds [ 21 ]. Different sources indicate different percentages of Wistar rats sensitive to sound, from 15 to 50%; apparently, sensitivity varies considerably in different Wistar substrains maintained in isolation in different catteries for many years [ 121 , 136 ]. Subsequently, a similar phenomenon of AE-proneness was found in mice [ 137 , 138 ].…”

“…In WAR, the stable AE phenotype is present at the age of 70–78 days [ 25 ]. The cDNA microarray and RNA-seq methods identified the genetic abnormalities in connection with AE-proneness in these strains, followed by mutations in exon sequences, determining the expression of a wide range of genes and differences in the activity of key signaling pathways, demonstrated by the comparison of AE-prone and control strains [ 121 , 230 , 231 , 232 , 233 ]. In WAR and GASH/Sal, the transcriptome of the IC, the structure, determining the start of AE seizure, was analyzed for both groups—animals not exposed to sound (naïve) and for animals after a seizure [ 230 , 234 ].…”

“…In WAR and GASH/Sal, the transcriptome of the IC, the structure, determining the start of AE seizure, was analyzed for both groups—animals not exposed to sound (naïve) and for animals after a seizure [ 230 , 234 ]. In KM rats, the transcriptome of the IC and SC of naïve animals was analyzed [ 121 ]. It is the profile of the transcriptome in naïve animals that is of maximal interest, as it allows to evaluate the contribution of various genes and signaling pathways to the AE-proneness.…”

“…It is the profile of the transcriptome in naïve animals that is of maximal interest, as it allows to evaluate the contribution of various genes and signaling pathways to the AE-proneness. On the other hand, changes in the genes expression levels after seizures may include those involved in the compensatory mechanisms of seizure consequences [ 121 ]. However, the identification of specific genes with mutations and/or changes in expression levels that lead to seizure development in epilepsy models with polygenic or unknown nature of inheritance using whole-genome analysis methods faces a fundamental issue which complicates the whole problem.…”