Audiogenic Epilepsy Research Articles

Active avoidance learning in rats with different audiogenic epilepsy proneness

The success of the formation of the conditioned reflex reaction of two-way avoidance in the shuttle chamber in rats of 3 strains was evaluated. These were rats predisposed to audiogenic epilepsy – the Krushinsky-Molodkina strain rats (KM), "4" strain (selected from a population of F2 hybrids of the KM strain and sound-insensitive Wistars) and rats of "0" strain, selected for the absence of audiogenic epilepsy from the same population (i. e. these strains, diametrically different in audiogenic epilepsy proneness, possessing a similar genetic background). Experiments have shown significantly more successful assimilation of this skill in rats of the "0" strain.

The involvement of proinflammatory cytokines in the pathogenesis of audiogenic epilepsy

Epilepsy is a heterogeneous disease, which determines the relevance of investigating the mechanisms of pathogenesis of its various types, including reflex epilepsy. Pharmacotherapy is common for the treatment of patients with epilepsy, however, despite the significant recent achievements, 20-30% of patients remain resistant to the ongoing treatment. The urgency of creating new antiepileptic drugs, in particular, immune ones is due not only to a significant proportion of pharmacoresistant cases, but also to the struggle for the quality of life of patients. The neuroinflammation system in animals with different genetically determined audiogenic epilepsy proneness was investigated. These genetic groups were Krushinsky–Molodkina rats (tonic seizures of maximum intensity in response to the action of sound) and “0” strain (control group, non-convulsive phenotype). The main proinflammatory cytokines levels in the dorsal striatum and brain stem in rats of these genetic groups were measured by multiplex immunofluorescence assay. Background levels of IL-1â, IL-6 and TNFá in the dorsal striatum of KM rats were significantly lower than in the control “0” strain rats, whereas in the brain stem in the “background” levels of these metabolites did not differ. Four hours after the sound exposure, the TNFá level in the dorsal striatum of KM rats was significantly lower than in “0” rats. In KM rats, after the sound exposure and subsequent tonic seizures, the levels of IL-1â and IL-6 in the dorsal striatum were significantly higher than in the background. The IL-2 content was not detected in the background in KM rats, whereas after audiogenic seizures its level was 14.01 pg/ml. In the brain stem of KM rats, the levels of IL-1â and TNFá after audiogenic seizures were significantly lower than in the background. In rats of the “0” strain, cytokine levels in the dorsal striatum after the sound exposure did not differ from those in the background, while IL-1ß levels in their brain stem were significantly lower than the background state. Particular modulating role of the studied proinflammatory cytokines in the pathogenesis of audiogenic epilepsy is assumed, as well as certain possibility of anti-inflammatory and immune drugs application in anticonvulsant and antiepileptic therapy.

Investigating the Therapeutic Property of Galium verum L. (GV) for MSG induced Audiogenic Epilepsy (AEs) and Neuroprotection through In-Silico and In-Vitro Analysis.

Audiogenic Epilepsy (AEs) is a subtype of epileptic seizure that is generally caused by high-intensity sounds. A large number of traditional medicines has been explored in this lieu where our study chased Galium verum L. (Rubiaceae), an herbal plant which is commonly known as Lady's Bedstraw, that contains a highly rich chemical composition including flavonoids (Hispidulin, Quercetin, and Kaempferol), and phenolic acids (chlorogenic acid, caftaric acid, and gallic acid). G verum is well known for its antioxidant, neuroprotective, and anti-inflammatory properties. Recently, the unique role of Adhesion G Protein- Coupled Receptor V1 (ADGRV1) protein in the progression of audiogenic epilepsy has been explored. This study aimed to examine the potent phytoconstituents of the hydroalcoholic extract of G. verum L. (HEGV) using analytical techniques. Additionally, our study sought to evaluate the antioxidant, neuroprotective, anti-inflammatory properties, and antiepileptic potency of HEGV by targeting ADGRV1 via in silico and in vitro analyses using SHSY5Y cells. HPLC and LC-MS techniques were employed to identify the flavonoids, iridoids, and phenolic acid derivatives present in HEGV. DPPH (2,2-diphenyl-1-picrylhydrazyl), nitric oxide (NO), and hydroxyl (OH) radical scavenging assays were performed to confirm the antioxidant potential of the extract. Additionally, in silico molecular docking and molecular dynamic studies were performed using AutoDock Vina software to analyze the possible interactions between crucial phytoconstituents of HEGV and ADGRV1, followed by cell line analysis. In the in vitro analysis, antioxidant, neuroprotective, and anti-inflammatory properties were assessed via cell viability assay, IL, GABA, and glutamate estimation. LC-MS and HPLC analyses revealed high concentrations of hispidulin, a major flavonoid found in HEGV. HEGV exhibited moderate-to-high free radical-scavenging activities comparable to those of ascorbic acid. Docking analysis demonstrated that hispidulin has a stronger binding affinity with ADGRV1 (Vina score = -8.6 kcal/mol) than other compounds. Furthermore, cell line analysis revealed that the MSG exacerbates the neurodegeneration and neuroinflammation, whereas, HEGV and Hispidulin both possess neuroprotective, antioxidant, and antiepileptic activities. HEGV and Hispidulin proved to be promising candidates for treating audiogenic epilepsy by modulating ADGRV1.

Active Avoidance Learning in Rats with Different Audiogenic Epilepsy Proneness

Active Avoidance Learning in Rats with Different Audiogenic Epilepsy Proneness

Wireless EEG Recording of Audiogenic Seizure Activity in Freely Moving Krushinsky-Molodkina Rats.

This study investigates audiogenic epilepsy in Krushinsky-Molodkina (KM) rats, questioning the efficacy of conventional EEG techniques in capturing seizures during animal restraint. Using a wireless EEG system that allows unrestricted movement, our aim was to gather ecologically valid data. Nine male KM rats, prone to audiogenic seizures, received implants of wireless EEG transmitters that target specific seizure-related brain regions. These regions included the inferior colliculus (IC), pontine reticular nucleus, oral part (PnO), ventrolateral periaqueductal gray (VLPAG), dorsal area of the secondary auditory cortex (AuD), and motor cortex (M1), facilitating seizure observation without movement constraints. Our findings indicate that targeted neural intervention via electrode implantation significantly reduced convulsive seizures in approximately half of the subjects, suggesting therapeutic potential. Furthermore, the amplitude of brain activity in the IC, PnO, and AuD upon audiogenic stimulus onset significantly influenced seizure severity and nature, highlighting these areas as pivotal for epileptic propagation. Severe cases exhibited dual waves of seizure generalization, indicative of intricate neural network interactions. Distinctive interplay between specific brain regions, disrupted during convulsive activity, suggests neural circuit reconfiguration in response to escalating seizure intensity. These discoveries challenge conventional methodologies, opening avenues for novel approaches in epilepsy research and therapeutic interventions.

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy.

Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca2+ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca2+-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation-inhibition balance in the brain, and it can serve as a mouse model of epilepsy.

Postnatal development of the hippocampal GABAergic system in rats genetically prone to audiogenic seizures.

Epileptogenesis can be associated with altered genetic control of the GABAergic system. Here we analyzed Krushinsky-Molodkina (KM) rats genetically prone to audiogenic epilepsy. KM rats express fully formed audiogenic seizures (AGSs) not early, then they reach 3months. At the age of 1-2months, KM rats either do not express AGS or demonstrate an incomplete pattern of seizure. Such long-term development of AGS susceptibility makes KM rats an especially convenient model to investigate the mechanisms and dynamics of the development of inherited epilepsy. The analysis of the GABAergic system of the hippocampus of KM rats was done during postnatal development at the 15th, 60th, and 120th postnatal days. Wistar rats of corresponding ages were used as a control. In the hippocampus of KM pups, we observed a decrease in the expression of glutamic acid decarboxylase 67 (GAD67) and parvalbumin (PV), which points to a decrease in the activity of GABAergic neurons. Analysis of the 2-month-old KM rats showed an increase in GAD67 and PV expression while synapsin I and vesicular GABA transporter (VGAT) were decreased. In adult KM rats, the expression of GAD67, PV, and synapsin I was upregulated. Altogether, the obtained data indicate significant alterations in GABAergic transmission in the hippocampus of audiogenic KM rats during the first postnatal months.

Intracortical functional connectivity dynamics induced by reflex seizures

Functional connectivity analysis is gaining more interest due to its promising clinical applications. To study network mechanisms underlying seizure termination and postictal depression, we explore dynamics of interhemispheric functional connectivity near the offset of focal and bilateral seizures in the experimental model of reflex audiogenic epilepsy. In the model, seizures and spreading depression are induced by sound stimulation of genetically predisposed rodents. We characterize temporal evolution of seizure-associated coupling dynamics in the frontoparietal cortex during late ictal, immediate postictal and interictal resting states, using two measures applied to local field potentials recorded in awake epileptic rats. Signals were analyzed with mean phase coherence index in delta (1–4 Hz), theta (4–10 Hz) beta (10–25 Hz) and gamma (25–50 Hz) frequency bands and mutual information function. The study shows that reflex seizures elicit highly dynamic changes in interhemispheric functional coupling with seizure-, region- and frequency-specific patterns of increased and decreased connectivity during late ictal and immediate postictal periods. Also, secondary generalization of recurrent seizures (kindling) is associated with pronounced alterations in resting-state functional connectivity – an early wideband decrease and a subsequent beta-gamma increase. The findings show that intracortical functional connectivity is dynamically modified in response to seizures on short and long timescales, suggesting the existence of activity-dependent plastic network alterations that may promote or prevent seizure propagation within the cortex and underlie postictal behavioral impairments.

Dysregulation of GABAergic System in the Inferior Colliculi of Rats during the Development of Audiogenic Epilepsy

Dysregulation of GABAergic System in the Inferior Colliculi of Rats during the Development of Audiogenic Epilepsy

Dysregulation of GABAergic System in the Inferior Colliculi of Rats during the Development of Audiogenic Epilepsy

Epilepsy is tightly associated with dysfunction of inhibitory GABA neurotransmission. In this study, Krushinsky–Molodkina (KM) rats genetically prone to audiogenic seizures (AGS) were used. KM rats are characterized by the development of audiogenic epilepsy during postnatal ontogenesis, with AGS onset at the age of 1.5–2 months and fully developed AGS expression by 3rd month. We analyzed GABAergic system of the inferior colliculi (IC) of KM rats at different stages of postnatal development. Wistar rats were used as a control. In the IC of young KM rats, Na+/K+/Cl– cotransporter 1 (NKCC1) expression was increased, while K+/Cl– cotransporter 2 (KCC2) was unchanged indicating impairment of postsynaptic GABA action at early stages of postnatal development. Moreover, we revealed also an increase in the expression of vesicular GABA transporter (VGAT) in the IC which additionally pointed on the higher activity of GABA release. In adult rats, in opposite, we revealed a decrease in the expression of KCC2 transporter indicating downregulation of GABA inhibition on the target cells. Thus, GABA dysregulation in the IC can mediate the seizure susceptibility in adult KM rats.

Animal Models of Hypertension (ISIAH Rats), Catatonia (GC Rats), and Audiogenic Epilepsy (PM Rats) Developed by Breeding.

Research into genetic and physiological mechanisms of widespread disorders such as arterial hypertension as well as neuropsychiatric and other human diseases is urgently needed in academic and practical medicine and in the field of biology. Nevertheless, such studies have many limitations and pose difficulties that can be overcome by using animal models. To date, for the purposes of creating animal models of human pathologies, several approaches have been used: pharmacological/chemical intervention; surgical procedures; genetic technologies for creating transgenic animals, knockouts, or knockdowns; and breeding. Although some of these approaches are good for certain research aims, they have many drawbacks, the greatest being a strong perturbation (in a biological system) that, along with the expected effect, exerts side effects in the study. Therefore, for investigating the pathogenesis of a disease, models obtained using genetic selection for a target trait are of high value as this approach allows for the creation of a model with a "natural" manifestation of the pathology. In this review, three rat models are described: ISIAH rats (arterial hypertension), GC rats (catatonia), and PM rats (audiogenic epilepsy), which are developed by breeding in the Laboratory of Evolutionary Genetics at the Institute of Cytology and Genetics (the Siberian Branch of the Russian Academy of Sciences).

Effect of Taurine on the Manifestations of Audiogenic Epilepsy in Rats with Pendulum Movements

Effect of Taurine on the Manifestations of Audiogenic Epilepsy in Rats with Pendulum Movements

Neuroinflammation in the pathogenesis of the audiogenic epilepsy: altered proinflammatory cytokine levels in Krushinsky-Molodkina seizure-prone rats

Neuroinflammation plays an important role in epileptogenesis, however, most studies are performed on pharmacological models of epilepsy, while data on non-invasive, including genetic, models are practically absent. In Krushinsky-Molodkina (KM) strain rats with high genetically caused predisposition to AE (intensive audiogenic seizure fit in response to the action of sound) and in the control strain “0” (not predisposed to AE), the levels of a number of pro-inflammatory cytokines were investigated using multiplex immunofluorescence magnetic assay (MILLIPLEX map Kit). Cytokine levels were determined in the dorsal striatum tissue and in the brain stem. Background levels of IL-1β, IL-6 and TNF-α in the dorsal striatum of KM rats were significantly lower than in rats “0” (32.31, 27.84 and 38.87% of decrease, respectively, p < 0.05, 0.05 and 0.01), whereas in the brain stem in the “background” state of interstrain differences in levels of these metabolites were not detected. 4 h after sound exposure, the TNF-α level in the dorsal striatum of KM rats was significantly (38.34%, p < 0.01) lower than in “0” rats. In KM rats, after the action of sound and the subsequent seizure fit, the levels of IL-1β and IL-6 in the dorsal striatum were significantly higher compared to the background (35.29 and 50.21%, of increase, p < 0.05, 0.01, respectively). The IL-2 level in KM rats in the background state was not detected, whereas after audiogenic seizures its level was 14.01 pg/ml (significantly higher, p < 0.01). In the brain stem of KM rats, the levels of IL-1β and TNF-α after audiogenic seizures were significantly lower than in the background (13.23 and 23.44% of decrease, respectively, p < 0.05). In rats of the “0” strain, the levels of cytokines in the dorsal striatum after the action of sound (which did not cause AE seizures) did not differ from those in the background, while the levels of IL-1β in their brain stem were lower than in the background (40.28%, p < 0.01). Thus, the differences between the background levels of cytokines and those after the action of sound were different in rats that differed in their predisposition to AE, which suggests the involvement of these metabolites in the pathophysiology of epilepsy.

Neuroinflammation in Pathogenesis of Audiogenic Epilepsy: Altered Proinflammatory Cytokine Levels in the Rats of Krushinsky–Molodkina Seizure-Prone Strain

Neuroinflammation plays an important role in epileptogenesis, however, most studies are performed using pharmacological models of epilepsy, while there are only few data available for non-invasive, including genetic, models. The levels of a number of pro-inflammatory cytokines were examined in the Krushinsky-Molodkina (KM) rat strain with high audiogenic epilepsy (AE) proneness (intense tonic seizure fit in response to loud sound) and in the control strain "0" (not predisposed to AE) using multiplex immunofluorescence magnetic assay (MILLIPLEX map Kit). Cytokine levels were determined in the dorsal striatum tissue and in the brain stem. Background levels of IL-1β, IL-6, and TNF-α in the dorsal striatum of the KM rats were significantly lower than in the rats "0" (by 32.31, 27.84, and 38.87%, respectively, p < 0.05, 0.05, and 0.01), whereas no inter-strain differences in the levels of these metabolites were detected in the brain stem in the "background" state. Four hours after sound exposure, the TNF-α level in the dorsal striatum of the KM rats was significantly lower (by 38.34%, p < 0.01) than in the "0" rats. In the KM rats, the dorsal striatal levels of IL-1β and IL-6 were significantly higher after the sound exposure and subsequent seizure fit, compared to the background (35.29 and 50.21% increase, p < 0.05, 0.01, respectively). In the background state the IL-2 level in the KM rats was not detected, whereas after audiogenic seizures its level was 14.01 pg/ml (significant difference, p < 0.01). In the KM rats the brain stem levels of IL-1β and TNF-α after audiogenic seizures were significantly lower than in the background (13.23 and 23.44% decrease, respectively, p < 0.05). In the rats of the "0" strain, the levels of cytokines in the dorsal striatum after the action of sound (which did not induce AE seizures) were not different from those of the background, while in the brain stem of the "0" strain the levels of IL-1β were lower than in the background (40.28%, p < 0.01). Thus, the differences between the background levels of cytokines and those after the action of sound were different in the rats with different proneness to AE. These data suggest involvement of the analyzed cytokines in pathophysiology of the seizure state, namely in AE seizures.

Brain D2-Like Dopamine Receptor Distribution in Rats with Different Types of Genetic Epilepsy.

The distribution of the D2-like dopamine receptor (D2DR) in the cortex and striatum was compared between rats with absence, audiogenic, or combined genetically determined epilepsy and normal Wistar rats by autoradiography. A significantly lower D2DR binding density was observed in the dorsal and ventrolateral aspects of the nucleus accumbens in epileptic vs. non-epileptic rats. Rats with audiogenic epilepsy additionally showed a higher D2DR density in the dorsal striatum and motor and somatosensory cortex and a lower D2DR density in the ventrolateral part of the nucleus accumbens. The findings indicated that a common neuronal circuit is involved in the pathogenesis of both convulsive and nonconvulsive forms of generalized epilepsy.

Role of Brain Monoamines in the Formation of Audiogenic Myoclonic Seizures in Krushinsky–Molodkina Rats

The results demonstrate and confirm the significant role of monoamine imbalance in the ictogenesis of Krushinsky–Molodkina rats with genetically determined audiogenic epilepsy and in the development of audiogenic kindling (AuK) in them. The experiments were carried out on rats of the Krushinsky–Molodkina (KM) line without sound stimulation (KM-background) and after the development of AuK (KM-AuK). The control group was rats of line “0”, in which convulsions in response to sound were completely absent. AuK was generated using 20-fold sound stimulation (120 dB). Neurochemical analysis was performed by HPLC/ED in the frontal cortex, hippocampus, hypothalamus, nucleus accumbens, and brainstem. It has been established that AuK in KM rats leads to the appearance of myoclonic and attenuation of stem convulsions, which is accompanied by a change in the functional activity of the noradrenergic and serotonergic systems of the brain. KM rats exhibiting tonic convulsions in the “background” have a low content of norepinephrine in the hippocampus and hypothalamus, and when audiogenic myoclonic convulsions develop, norepinephrine deficiency is observed in the frontal cortex. After the formation of AuK, the excessively intense serotonin metabolism revealed in KM slows down in the hippocampus, nucleus accumbens, and, especially, in the brainstem, and the serotonin deficiency in the striatum also disappears. The peculiarities of norepinephrine metabolism in KM rats before and after AuK emphasize the important role of the cortex in the development of myoclonic convulsions, and of the hippocampus and hypothalamus in the implementation of stem convulsions. Excessive functional activity of the serotonergic system, revealed in KM “background” rats, slows down in a number of brain structures during the production of AuK.

EFFECT OF TAURINE ON MANIFESTATION OF AUDIOGENIC EPILEPSY IN RATS WITH PENDULUM MOVEMENTS

A decrease of taurine in hippocampus of the line of rats with pendulum movements (PM), predisposed to audiogenic epilepsy, was shown. Taurine (aminoethanesulfonic acid) is known to be an anticonvulsant drug. The aim of the present work was to verify the predictive validity of taurine in rats with pendulum movements (PM). In neonatal period the exogenous taurine administration did not influence a convulsive activity at the age of 1.5 and 3 months in PM rats. The increase in the number of audiogenic seizures after taurine injections was found in adolescent period in 1.5 months and in prolonged point – in 3 months. The number of abortive seizures decreased under acute injection of taurine in adult PM rats, but the level of ictal and postictal indicators restored one month later, at the age of 4 months. Obtained results indicate the absence of effect of taurine administered to rats in the neonatal age, while at the long-term scale, the rats showed the increasing seizure activity under the action of taurine in adolescent period and confirm the predictive validity of this drug in adult PM rats.

Social Behavioral Deficits in Krushinsky-Molodkina Rats, an Animal Model of Audiogenic Epilepsy.

In clinical practice, epilepsy is often comorbid with the autism spectrum disorders (ASDs). This warrants a search of animal models to uncover putative overlapping neuronal mechanisms. The Krushinsky-Molodkina (KM) rat strain is one of the oldest inbred animal models for human convulsive epilepsies. We analyzed the behavioral response of adult seizure-naive KM males in three-chambered tests for social preference. We found that a presence of social stimuli (encaged unfamiliar Wistar rats of the same age and sex) evoked a reduced or reversed exploratory response in freely moving KM individuals. The epilepsy-prone rats demonstrated remarkably shortened bouts of social contacts and displayed less locomotion around the stranger rat-containing boxes, together with a pronounced freezing response. The decrease in social preference was not due to a general decrease in activity, since relative measures of activity, the index of sociability, were decreased, too. The susceptibility to audiogenic seizures was verified in the KM cohort but not seen in the control Wistar group. We propose the KM rat strain as a new animal model for comorbid ASD and epilepsy.

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

Animal models of epilepsy are of great importance in epileptology. They are used to study the mechanisms of epileptogenesis, and search for new genes and regulatory pathways involved in the development of epilepsy as well as screening new antiepileptic drugs. Today, many methods of modeling epilepsy in animals are used, including electroconvulsive, pharmacological in intact animals, and genetic, with the predisposition for spontaneous or refractory epileptic seizures. Due to the simplicity of manipulation and universality, genetic models of audiogenic epilepsy in rodents stand out among this diversity. We tried to combine data on the genetics of audiogenic epilepsy in rodents, the relevance of various models of audiogenic epilepsy to certain epileptic syndromes in humans, and the advantages of using of rodent strains predisposed to audiogenic epilepsy in current epileptology.

Characteristic Features of the Transcriptome in a Rat Strain with Audiogenic Epilepsy

Audiogenic epilepsy (AE), developing in rodent strains in response to sound, is widely used as the model of generalized convulsive epilepsy, while the molecular mechanisms determining AE are currently poorly understood. The brain region that is crucial for AE development isthe inferior and superior colliculi (IC, SC). We compared IC-SC gene expression profiles in rats with different AE susceptibility using transcriptome analysis.The transcriptomes were obtained from the IC-SC of Wistar rats (with no AE), Krushinsky-Molodkina (KM) strain rats (100% AE susceptible), and ”0” strain rats (with no AE) selected from F2 KM x Wistar hybrids for AE absence. KM gene expression displayed characteristic differences inboth of the strains that were not susceptible to AE. There was increased expression of a number of genes responsible for positive regulation of the MAPK signaling cascade, as well as of genes responsible for the production of interferon and several other cytokines. An increase in the expression levels of theTTR gene was found in KM rats, as well as significantly lower expression of the Msh3 gene (involved in post-replicative DNA repair systems). AE was also describedin the 101/HY mouse strain with a mutation in the locus controlling DNA repair. The DNA repair system defects could be the primary factor leading to the accumulation of mutations, which, in turn, promote AE.&#x0D; Keywords: udiogenic seizure, KM strain, transcriptome, TTR gene, Msh3 gene, DNA repair