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Regulation of intracellar Ca^<2+> concentration and transcription factors in absence seizures

失神发作时细胞内 Ca^2 浓度和转录因子的调节

基本信息

批准号：
09670108
负责人：
ITO Yoshihisa
金额：
$ 1.34万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670108/
关键词：
Absence seizures GABA_B receptor Lethargic Mice Stargazer mice spikeamd wave discharges DNA-binding activity 欠神発作 Cyclic AMP responsive element Activator protein 1 CGP 46381 視床棘徐波複合エトクスシミド GABA_B拮抗薬 stargazerマウス lethargicマウ

项目摘要

In this study, I examined the involvement of the GABA_B receptors and the coordinated induction of nuclear transcription factors in generalized absence seizures in lethargic (lh/lh) and stargazer (stg/stg) mice, genetic models of absence seizures. electroencephalographic recordings of lethargic and stargazer mice revealed 6 Hz spike and wave discharges (SWD_S) accompanied by simultaneous arrest of movement for the duration of the SWDs. Ethosuximide, a typical antiabsence drug, and CGP 35348 and CGP 46381, GABA_B antagonist, suppressed SWD_S in both models Gel-shift assays showed that nuclear cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in the thalamus and cerebral cortex, but not in other regions such as the cerebellum of lethargic and stargazer mice were significantly higher than those of each nonepileptic control (+/+) mice. The CRE- and AP-1 DNA-binding activities in both model mice, but not control mice, were inhibited by ethosuximide or CGP 46831, at a dose which suppressed SWD_S. These results suggest that GABA_B receptors play a significant role in the pathogenesis of generalized absence seizures and that enhanced nuclear CRE- and AP-1 DNA-binding activities in the thalamocortical region are related to generation and/or propagation of absence seizures in lethargic and stargazer mice. Furthermore, cerebral cortical CRE-binding activity was supershifted by the anti-GRE-binding protein (CREB) antibody and partially inhibited by anti-phospho-CREB antibody in lethargic mice. The AP-1 DNA-binding activity was inhibited by anti-c-Fos and anti-c-Jun antibodies.These results suggest that the enhanced CRE-binding activity is attributable to the activation of the binding activity of CREB which is phosphorylated at least in part and that the c-Fos-c-Jun complex (AP-1 protein) is a major component of the enhanced AP-1 DNA-binding activity.

在这项研究中，我检查了GABA_B受体的参与和核转录因子的协调诱导在嗜睡（lh/lh）和stargazer（stg/stg）小鼠，失神发作的遗传模型中的全身失神发作。昏睡和观星小鼠的脑电图记录显示6 Hz尖峰和波放电（SWD_S），伴随着在SWD持续时间内的运动的同时停止。抗失神药乙琥胺和GABA_（B）拮抗剂CGP 35348和CGP 46381均能抑制SWD_S。而在其他区域如小脑中，嗜睡和观星小鼠的细胞凋亡率显著高于每个非癫痫对照（+/+）小鼠。在抑制SWD_S的剂量下，乙琥胺或CGP 46831可抑制两种模型小鼠的CRE和AP-1DNA结合活性，而对照小鼠则无此作用。这些结果提示GABA_（B）受体在失神发作的发病机制中起重要作用，丘脑皮质区CRE和AP-1核DNA结合活性的增强与嗜睡和观星小鼠失神发作的发生和/或传播有关。此外，大脑皮层的CREB结合活性超移位的抗GRE结合蛋白（CREB）抗体和抗磷酸化CREB抗体在昏睡小鼠部分抑制。抗c-Fos和抗c-Jun抗体均能抑制AP-1的DNA结合活性，提示CRE结合活性的增强是由于磷酸化的CREB的结合活性被激活，而c-Fos-c-Jun复合物（AP-1蛋白）是AP-1 DNA结合活性增强的主要成分。