Dataset Information

Putative Causal Variant on Vlgr1 for the Epileptic Phenotype in the Model Wistar Audiogenic Rat.

ABSTRACT: Wistar Audiogenic Rat is an epilepsy model whose animals are predisposed to develop seizures induced by acoustic stimulation. This model was developed by selective reproduction and presents a consistent genetic profile due to the several generations of inbreeding. In this study, we performed an analysis of WAR RNA-Seq data, aiming identified at genetic variants that may be involved in the epileptic phenotype. Seventeen thousand eighty-five predicted variants were identified as unique to the WAR model, of which 15,915 variants are SNPs and 1,170 INDELs. We filter the predicted variants by pre-established criteria and selected five for validation by Sanger sequencing. The genetic variant c.14198T>C in the Vlgr1 gene was confirmed in the WAR model. Vlgr1 encodes an adhesion receptor that is involved in the myelination process, in the development of stereocilia of the inner ear, and was already associated with the audiogenic seizures presented by the mice Frings. The transcriptional quantification of Vlgr1 revealed the downregulation this gene in the corpus quadrigeminum of WAR, and the protein modeling predicted that the mutated residue alters the structure of a domain of the VLGR1 receptor. We believe that Vlgr1 gene may be related to the predisposition of WAR to seizures and suggest the mutation Vlgr1/Q4695R as putative causal variant, and the first molecular marker of the WAR strain.

SUBMITTER: Damasceno S

PROVIDER: S-EPMC8220163 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Putative Causal Variant on <i>Vlgr1</i> for the Epileptic Phenotype in the Model Wistar Audiogenic Rat.

Damasceno Samara S Fonseca Pablo Augusto de Souza PAS Rosse Izinara Cruz IC Moraes Márcio Flávio Dutra MFD de Oliveira José Antônio Cortes JAC Garcia-Cairasco Norberto N Brunialti Godard Ana Lúcia AL

Frontiers in neurology 20210609

Wistar Audiogenic Rat is an epilepsy model whose animals are predisposed to develop seizures induced by acoustic stimulation. This model was developed by selective reproduction and presents a consistent genetic profile due to the several generations of inbreeding. In this study, we performed an analysis of WAR RNA-Seq data, aiming identified at genetic variants that may be involved in the epileptic phenotype. Seventeen thousand eighty-five predicted variants were identified as unique to the WAR ...[more]

PMID: 34177758

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Project description:Audiogenic epilepsy (AE), developing in rodent strains in response to loud sound, is widely used as the model of generalized convulsive epilepsy. The molecular and genetic mechanisms that determine the expression of AE are currently non well understood. In the present work we compared transcriptomes from the inferior and superior colliculi (corpora quadrigemina), the crucial epileptogenic midbrain zone for AE in order to identify genes associated to the AE phenotype. Transcriptomes of rats from three strains were compared: Krushinsky-Molodkina (KM) strain (100% AE-prone); Wistar outbred rats (with no AE proneness) and "0" strain, selected from F2 KMxWistar hybrids for the lack of AE. It is shown that KM strain gene expression profile have a number of characteristic differences from those of Wistar and "0" strains. In particular, KM has increased expression of a number of genes involved in positive regulation of the MAPK signaling cascade, as well as genes, responsible for positive regulation of apoptotic processes. The next characteristic difference between the KM strain from Wistar and "0" is a multiple increase in the expression level of the Ttr gene, which is known to be associated with family amyloid polyneuropathy in humans. Further, the KM strain showed a significant decrease in the expression of the Msh3 gene involved in the DNA mismatch repair system, Acsm5, coding a mitochondrial acyl-CoA synthetase specific for medium chain family member 5, and in a number of genes of the oxidative phosphorylation system, and a number of some other genes. Our data confirm the complex multigenic nature of AE inheritance in rodents. A comparison with the data obtained from other AE rodent strains suggests that the convulsive phenotype could develop differently in audiogenic rat strains selected independently. Although, the finding of parallel differences in certain genes expression in AE-prone hamsters (another rodent species) indicate the common (and crucial) neurogenetic defects, leading to AE phenotype in rodents in general.

Project description:Neuroinflammation is a key component of epileptogenesis, the process leading to acquired epilepsy. In recent years, with the development of non-invasive in vivo positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO), a marker of neuroinflammation, it has become possible to perform longitudinal studies to characterize neuroinflammation at different disease stages in animal models of epileptogenesis. This study aimed to utilize the prognostic capability of TSPO PET imaging at disease onset (2 weeks post-SE) to categorize epileptic rats with distinct seizure burden based on TSPO levels at disease onset and investigate their association to TSPO expression at the chronic epilepsy stage. Controls (n = 14) and kainic acid-induced status epilepticus (KASE) rats (n = 41) were scanned non-invasively with [18F]PBR111 PET imaging measuring TSPO expression. Animals were monitored using video-electroencephalography (vEEG) up to chronic disease (12 weeks post-SE), at which TSPO levels ([3H]PK11195) as well as other post-mortem abnormalities (namely synaptic density ([3H]UCB-J), neuronal loss (NeuN), and neurodegeneration (FjC)) were investigated. By applying multivariate analysis, TSPO PET imaging at disease onset identified three KASE groups with significantly different spontaneous recurrent seizures (SRS) burden (defined as rare SRS, sporadic SRS, and frequent SRS) (p = 0.003). Interestingly, TSPO levels were significantly different when comparing the three KASE groups (p < 0.0001), with the frequent SRS group characterized only by a limited focal TSPO increase at disease onset. On the contrary, TSPO measured during chronic epilepsy was found to be the highest in the frequent SRS group and correlated with seizure burden (r = 0.826, p < 0.0001). Importantly, early and chronic TSPO levels did not correlate (r = -0.05). Finally, significant pathological changes in neuronal loss, synaptic density, and neurodegeneration were found not only when compared to control animals (p < 0.01), but also between the three KASE rat categories in the hippocampus (p < 0.05). Early and chronic TSPO upregulation following epileptogenic insult appear to be driven by two superimposed dynamic processes. The former is associated with epileptogenesis as measured at disease onset, while the latter is related to seizure frequency as quantified during chronic epilepsy.

Dataset Information

Putative Causal Variant on Vlgr1 for the Epileptic Phenotype in the Model Wistar Audiogenic Rat.

Publications

Putative Causal Variant on <i>Vlgr1</i> for the Epileptic Phenotype in the Model Wistar Audiogenic Rat.

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