Identification of Novel Mutations Controlling Cerebral Cortex Malformations Caused by ENU-Induced Mutagenesis in the Mouse

Борисова, Е. В.; Epifanova, Ekaterina A.; Tutukova, S.A.; Belousova, І. A.; Zhidkova, Natalia; Rusanova, Anastasiia; Salina, V. A.; Turovsky, Egor A.; Turovskaya, M. V.; Tarabykin, Victor; Бабаев, А.А.

doi:10.17691/stm2018.10.3.8

Cited by 5 publications

(4 citation statements)

References 15 publications

(21 reference statements)

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“…The intensity of seizure activity manifestation in response to sound stimulation was assessed according to the Krushinsky scale [ 31 , 36 ]. In addition to assessing the intensity of the seizures, the number of fatalities was also assessed.…”

Section: Methodsmentioning

confidence: 99%

The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

et al. 2022

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The high prevalence of diagnosed cases of severe neurological disorders, a significant proportion of which are epilepsy, contributes to a high level of mortality and disability in the population. Neurotrophic factors BDNF and GNDF are considered promising agents aimed at increasing the central nervous system’s adaptive potential for the development of the epileptiform activity. Despite the pronounced neuroprotective and anticonvulsant potential, an appropriate way to stimulate these endogenous signaling molecules with minimal risk of side effects remains an open question. Herein, we assessed the safety of gene therapy using original adeno-associated viral constructs carrying the genes of neurotrophic factors BDNF and GDNF in the early postnatal period of development of experimental animals. The intraventricular injection of AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs into newborn mice was found to provide persistent overexpression of target genes in the hippocampus and cerebral cortex in vivo for four weeks after injection. The application of viral constructs has a multidirectional effect on the weight and body length characteristics of mice in the early postnatal period; however, it ensures the animals’ resistance to the development of seizure activity under audiogenic stimulation in the late postnatal period and preserves basic behavioral reactions, emotional status, as well as the mnestic and cognitive abilities of mice after simulated stress. Our results demonstrated the safety of using the AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs in vivo, which indicates the expediency of further testing the constructs as therapeutic anticonvulsants.

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Section: Methodsmentioning

confidence: 99%

The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

et al. 2022

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“…In order to identify novel gene alleles susceptible to audiogenic seizures, we carried out ENU-induced genetic screening [16,17]. As a result of a series of injections of ENU into C3H wild type mice, a novel mutant strain, socrates (soc), was generated.…”

Section: Characterization Of Epileptiform Activity and Behavior In A ...mentioning

confidence: 99%

“…The ENU (Sigma-Aldrich, Burlington, MA, USA) treatment was performed as previously described (Borisova et al, 2018). Briefly, 80 µg/kg of ENU was administered intraperitoneally to 8-week-old C3H/HeN mice.…”

Section: Generation Of the Soc Mouse Strain Using Enu-directed Mutage...mentioning

confidence: 99%

“…Mice were observed using a LifeCam Cinema HD video camera (Microsoft, Redmond, WA, USA). Testing of mice was carried out at the age of 21-25 days after birth (P21-P25), and it is described in more detail in a previous study [16,17]. Briefly, mice were presented with a single 110 dB sound from an electromechanical bell.…”

Section: Generation Of the Soc Mouse Strain Using Enu-directed Mutage...mentioning

confidence: 99%

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

Varlamova,

Borisova,

Evstratova

et al. 2023

IJMS

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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.

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Effect of Endogenous Expression of the Neurotrophic Factor BDNF on Epileptiform Activity

Anastasia,

Gavrish,

Borisova

et al. 2024

2024 Sixth International Conference Neurotechnologies and Neurointerfaces (CNN)

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Identification of Novel Mutations Controlling Cerebral Cortex Malformations Caused by ENU-Induced Mutagenesis in the Mouse

Cited by 5 publications

References 15 publications

The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

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

Effect of Endogenous Expression of the Neurotrophic Factor BDNF on Epileptiform Activity

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