Delayed audiogenic seizure development in a genetic rat model is associated with overactivation of ERK1/2 and disturbances in glutamatergic signaling

Chernigovskaya, E. V.; Korotkov, A.; Дорофеева, Н. А.; Gorbacheva, E. L.; Kulikov, Alexey A.; Глазова, М. В.

doi:10.1016/j.yebeh.2019.106494

Cited by 27 publications

(17 citation statements)

References 31 publications

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“…An imbalance between excitatory and inhibitory signals in the brain with excessive activity of excitatory glutamatergic system is one of the basic mechanisms of seizure susceptibility [35,36]. Our recent studies demonstrated increased glutamatergic transmission in the hippocampus of KM rats during the first month of postnatal development when the readiness to audiogenic seizures has not manifested yet [37]. These results indicate that the hyperactivity of glutamatergic system may be a result of aberrant glutamatergic differentiation of new-born cells in the hippocampus of KM rats.…”

Section: Discussionmentioning

confidence: 68%

“…In previous studies, we demonstrated an increase in VGLUT2 expression in the dentate gyrus of two-week old KM rats. However, in the dentate gyrus of one-month old KM rats expression of VGLUT2 was the same with Wistar rats [37]. Development of the dentate gyrus in rodents continues during two first weeks after birth and at the beginning is characterized by excessive formation of cells, which are then eliminated [39].…”

Section: Discussionmentioning

confidence: 84%

“…Here, we confirmed our in vivo data and demonstrated genetically determined glutamatergic differentiation fate of embryonic KM NPC in vitro. Previously, we have shown an increase in the expression of the NR2B subunit of N-methyl D-aspartate (NMDA) receptors in the hippocampus of two-week old KM pups [37]. It is known that not only neurons, but also astrocytes, both express glutamate receptors including NR2B [40] by which astrocytes synchronize Ca2+ signaling with neurons after the onset of epileptiform activity [41].…”

Section: Discussionmentioning

confidence: 98%

“…Development of the dentate gyrus in rodents continues during two first weeks after birth and at the beginning is characterized by excessive formation of cells, which are then eliminated [39]. The increase in VGLUT2 expression in the dentate gyrus of two-week old KM demonstrated aberrantly activate glutamatergic transmission [37] that revealed the predisposition of newly born cells to differentiate into glutamatergic neurons. Here, we confirmed our in vivo data and demonstrated genetically determined glutamatergic differentiation fate of embryonic KM NPC in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Glutamatergic Fate of Neural Progenitor Cells of Rats with Inherited Audiogenic Epilepsy

et al. 2020

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Epilepsy is associated with aberrant neurogenesis in the hippocampus and may underlie the development of hereditary epilepsy. In the present study, we analyzed the differentiation fate of neural progenitor cells (NPC), which were isolated from the hippocampus of embryos of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic epilepsy. NPCs from embryos of Wistar rats were used as the control. We found principal differences between Wistar and KM NPC in unstimulated controls: Wistar NPC culture contained both gamma-aminobutyric acid (GABA) and glutamatergic neurons; KM NPC culture was mainly represented by glutamatergic cells. The stimulation of glutamatergic differentiation of Wistar NPC resulted in a significant increase in glutamatergic cell number that was accompanied by the activation of protein kinase A. The stimulation of KM NPC led to a decrease in immature glutamatergic cell number and was associated with the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B/ glycogen synthase kinase 3 beta (Akt/GSK3β), which indicates the activation of glutamatergic cell maturation. These results suggest genetically programmed abnormalities in KM rats that determine the glutamatergic fate of NPC and contribute to the development of audiogenic epilepsy.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Glutamatergic Fate of Neural Progenitor Cells of Rats with Inherited Audiogenic Epilepsy

et al. 2020

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“…The ERK signaling pathway is activated by synaptic activity in learning and induction of LTP, but its activity is reduced in defected LTP and learning (49)(50)(51). Delayed audiogenic seizure development in a genetic rat model is associated with overactivation of ERK1/2 and disturbances in glutamatergic signaling (52). In the present study, it was found that the level of p-ERK1/2 was decreased after CMB model creation, and overexpression of CysC further decreased the level of p-ERK1/2, indicating that ERK signaling was involved in the promoting process of cognitive dysfunction in CMB rats due to CysC overexpression.…”

Section: Discussionmentioning

confidence: 99%

Cystatin C promotes cognitive dysfunction in rats with cerebral microbleeds by inhibiting the ERK/synapsin Ia/Ib pathway

Sun

et al. 2019

Exp Ther Med

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Although higher serum level of cystatin C (CysC) was observed in patients with cerebral microbleeds, its associated role in the disease has not been elucidated. In this work, a rat model of cerebral microbleeds was created with the aim of investigating effects of CysC on cognitive function in rats with cerebral microbleeds and the underlying mechanism. Serum samples of patients with cerebral microbleeds and healthy people of the same age were collected. Levels of cystatin C expression in these samples were measured using CysC kits. Moreover, 48 spontaneously hypertensive rats (SHRs) bred under specific pathogen-free (SPF) conditions were randomly divided into 4 groups: sham surgery control group (sham), model group (CMB), model + empty vector control group (CMB + vehicle), and model + cystatin C overexpression group (CMB + CysC). Expression levels of CysC in hippocampus of rats in each group were measured by western blot analysis. The Y-maze was used to evaluate cognitive function of rats. Hippocampal long-term potentiation (LTP) in rats was assessed by the electrophysiological assay. Alterations in levels of p-ERK1/2 and p-synapsin Ia/b proteins associated with cognitive function were identified by western blot analysis. The serum levels of CysC in patients with cerebral microbleeds were significantly upregulated (P<0.001). After injection of CysC, its expression levels in rat hippocampus were significantly increased (P<0.001), which enhanced the decline in learning and memory function, as well as the decrease of LTP in the rat model of cerebral microbleeds (P<0.001). Western blot results showed that injection of CysC further reduced the levels of p-ERK1/2 and p-synapsin Ia/b in the rat model of microbleeds (P<0.001). CysC was up regulated in serum of patients with cerebral microbleeds. It promoted cognitive dysfunction in rats with microbleeds by inhibiting ERK/synapsin Ia/Ib pathway.

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

Ivlev,

Naumova

2023

Intl J of Devlp Neuroscience

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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 3 months. At the age of 1–2 months, 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.

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Delayed audiogenic seizure development in a genetic rat model is associated with overactivation of ERK1/2 and disturbances in glutamatergic signaling

Cited by 27 publications

References 31 publications

Glutamatergic Fate of Neural Progenitor Cells of Rats with Inherited Audiogenic Epilepsy

Glutamatergic Fate of Neural Progenitor Cells of Rats with Inherited Audiogenic Epilepsy

Cystatin C promotes cognitive dysfunction in rats with cerebral microbleeds by inhibiting the ERK/synapsin Ia/Ib pathway

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

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