遗传性大鼠模型中听觉性癫痫发作发展延迟与 ERK1/2 的过度激活和谷氨酸能信号紊乱有关。
Delayed audiogenic seizure development in a genetic rat model is associated with overactivation of ERK1/2 and disturbances in glutamatergic signaling.
机构信息
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Thorez pr., 194223 St. Petersburg, Russia.
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Thorez pr., 194223 St. Petersburg, Russia.
出版信息
Epilepsy Behav. 2019 Oct;99:106494. doi: 10.1016/j.yebeh.2019.106494. Epub 2019 Sep 4.
Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizure are characterized by age-dependent expression of audiogenic seizures (AGS). It is known that the critical period of enhanced seizure susceptibility in rodents occurs at 2nd-3rd weeks of postnatal development. However, KM rats do not express AGS at this time-point, but start to demonstrate a stable AGS only after the age of 3 months. We hypothesized that this delay in AGS susceptibility in KM rats is genetically determined and may depend on some alterations in the development of the hippocampal glutamatergic system during the early postnatal period. We analyzed the expression and activity of seizure-related proteins, such as vesicular glutamate transporter 2 (VGLUT2), extracellular signal-regulated kinases 1 and 2 (ERK1/2), synapsin I, and NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor (NR2B) in the hippocampus of KM rats during postnatal development. A significantly higher activity of ERK1/2 in KM rats was observed at 14th, 30th, and 60th days of postnatal development (P14, P30, P60) in comparison with control Wistar rats of the corresponding ages, while in adult (P120) KM rats it was at the same level with Wistar rats. Despite the increased activity of ERK1/2 at P14 and P30, the phosphorylation of synapsin I at Ser62/67 was significantly lower in the hippocampus of KM rats than in Wistar rats of the same ages; however, at P60 and P120, the phosphorylation of synapsin I was enhanced. Our data also revealed the increase of VGLUT2 and NR2B expression at P14, which dramatically decreased at the later stages. Our data indicate that a genetically determined increase in ERK1/2 kinase activity during postnatal ontogenesis in KM rats may be associated with the disturbances in synthesis and activity of the proteins, which are responsible for glutamatergic transmission in the KM rat hippocampus during the seizure susceptibility development.
KM 大鼠具有听觉惊厥易感性，其听觉惊厥（AGS）的表达具有年龄依赖性。已知啮齿动物的易感性增强的关键时期发生在出生后第 2-3 周。然而，此时 KM 大鼠并不表现出 AGS，而是仅在 3 个月龄后才开始稳定地表现出 AGS。我们假设 KM 大鼠的这种 AGS 易感性延迟是由遗传决定的，可能取决于出生后早期海马谷氨酸能系统发育过程中的某些改变。我们分析了 KM 大鼠在出生后发育过程中，海马中与惊厥相关的蛋白质的表达和活性，如囊泡谷氨酸转运体 2（VGLUT2）、细胞外信号调节激酶 1 和 2（ERK1/2）、突触素 I 和 N-甲基-D-天冬氨酸（NMDA）受体（NR2B）的 NR2B 亚基。与相应年龄的对照 Wistar 大鼠相比，在 P14、P30 和 P60 时，KM 大鼠的 ERK1/2 活性明显更高（P14、P30、P60），而在成年（P120）KM 大鼠中，其活性与 Wistar 大鼠相同。尽管 ERK1/2 的活性在 P14 和 P30 时增加，但在 KM 大鼠的海马中，突触素 I 的 Ser62/67 磷酸化明显低于相同年龄的 Wistar 大鼠；然而，在 P60 和 P120 时，突触素 I 的磷酸化增强。我们的数据还显示，在 P14 时 VGLUT2 和 NR2B 表达增加，随后急剧减少。我们的数据表明，在 KM 大鼠的出生后发育过程中，ERK1/2 激酶活性的遗传决定增加可能与参与 KM 大鼠海马中谷氨酸能传递的蛋白质的合成和活性的紊乱有关。
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