Overexpression of the immediate-early genes Egr1, Egr2, and Egr3 in two strains of rodents susceptible to audiogenic seizures

López-López, Daniel; Gómez-Nieto, Ricardo; Herrero-Turrión, M.J.; García-Cairasco, Norberto; Sánchez-Benito, David; Ludeña, María Dolores; López, Dolores E.

doi:10.1016/j.yebeh.2015.12.020

Cited by 32 publications

(36 citation statements)

References 70 publications

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“…In the GASH/Sal model, overexpression of the immediate early genes Egr1 (Early Growth Response 1), Egr2 (Early Growth Response 2) and Egr3 (Early Growth Response 3) has been previously described [25]; however, little is known about the mutation responsible for susceptibility to seizures. We therefore characterized the underlying genetic variants of the GASH/ Sal strain by WES, a high-throughput, cost-effective method for the identification of diseasecausing mutations.…”

Section: Introductionmentioning

confidence: 99%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate-and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arh-gef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that PLOS ONE PLOS ONE | https://doi.

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Section: Introductionmentioning

confidence: 99%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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“…Neurochemical and molecular aspects have been investigated and suggest that GASH/Sal presents abnormalities in the GABAergic neurotransmission (15) as already proposed for the WAR model (16,17). Furthermore, López-López et al (18) revealed common molecular alterations, such as the overexpression of the Egr1, Egr2, and Egr3 genes in the IC of both models.…”

Section: Introductionmentioning

confidence: 77%

Top Common Differentially Expressed Genes in the Epileptogenic Nucleus of Two Strains of Rodents Susceptible to Audiogenic Seizures: WAR and GASH/Sal

et al. 2020

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“…The action of Egr1 in epileptogenesis goes beyond the regulation of Cacna2d4 as it promotes also the activation of Ca V 3.2, which has been previously demonstrated to convert hippocampal neurons hyperexcitable after SE (Becker et al, 2008). Previously, Egr1 was uncovered to contribute to several processes of epileptogenesis (Hughes and Dragunow, 1994;Beckmann et al, 1997;Rakhade et al, 2007;Helbig et al, 2008;Ló pez-Ló pez et al, 2017;Lösing et al, 2017), which makes this TF an ideal candidate for a powerful hub gene in an epileptogenic gene regulatory network and opens new vistas for pharmacological intervention by targeting the Egr1-pathway.…”

Section: Discussionmentioning

confidence: 99%

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis

et al. 2019

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Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca 2ϩ channel (VDCC) subunit Ca V 3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis. We found Egr1 to drive the expression of the VDCC subunit ␣2␦4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of ␣2␦4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 and ␣2␦4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of the VDCC subunits Ca V 3.2 and ␣2␦4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced "transcriptional Ca 2ϩ channelopathy."

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Overexpression of the immediate-early genes Egr1, Egr2, and Egr3 in two strains of rodents susceptible to audiogenic seizures

Cited by 32 publications

References 70 publications

Analysis of gene variants in the GASH/Sal model of epilepsy

Analysis of gene variants in the GASH/Sal model of epilepsy

Top Common Differentially Expressed Genes in the Epileptogenic Nucleus of Two Strains of Rodents Susceptible to Audiogenic Seizures: WAR and GASH/Sal

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis

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