Pumilio2-deficient mice show a predisposition for epilepsy.
Pumilio2-deficient mice show a predisposition for epilepsy.
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DOI：
10.1242/dmm.029678
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发表时间：
2017-11-01
影响因子：
4.3
通讯作者：
Kiebler MA
中科院分区：
文献类型：
--
作者：
Follwaczny P;Schieweck R;Riedemann T;Demleitner A;Straub T;Klemm AH;Bilban M;Sutor B;Popper B;Kiebler MA
癫痫是一种神经系统疾病，其由神经元集合的异常超同步活动引起，导致人类患者的复发性和自发性癫痫发作。增强的神经元兴奋性和神经元之间的高水平同步似乎触发了这些自发性癫痫发作。然而，关于神经元过度兴奋和癫痫维持的分子机制仍然知之甚少。在这里，我们表明，pumilio RNA结合家族成员2（Pumilio 2; Pum 2）在断奶和5个月大的雄性小鼠海马神经元兴奋性的调节中发挥作用。在成年Pum 2基因诱捕小鼠（Pum 2 GT）中几乎完全缺乏Pum 2会导致参与神经元兴奋性控制的基因失调。有趣的是，这一发现伴随着Pum 2 GT小鼠自发性癫痫发作的发展。此外，我们检测到Scn 1a（Nav1.1）和Scn 8a（Nav1.6）mRNA水平的年龄依赖性增加，以及Scn 2a（Nav1.2）转录水平的下降，在断奶的Pum 2 GT中，这在老年小鼠中是不存在的。此外，CA 1锥体神经元的现场记录显示出减少成对脉冲抑制的倾向后，刺激的Schaffer侧支连合通路在Pum 2 GT小鼠，表明在后期自发性癫痫发作的发展的倾向。随着5个月龄自发性癫痫发作的发生，我们检测到这些小鼠中Nav1.1和Nav1.2的蛋白水平增加以及Nav1.6的蛋白水平降低。 此外，GABA受体亚基α-2（Gabra 2）mRNA水平在断奶和成年小鼠中增加。此外，我们观察到增强的GABRA 2蛋白水平在树突状领域的CA 1亚区在Pum 2 GT海马。我们的结论是，已知的癫痫风险因素，如Nav1.1，Nav1.2，Nav1.6和GABRA 2的表达水平的改变导致癫痫发作的易感性和海马癫痫的表现增强。因此，我们的研究结果认为，Pum 2在癫痫发生和癫痫的维持中的作用。总结：致癫痫风险因素在Pumilio 2缺陷小鼠中被错误调节，决定了癫痫发作的易感性。这篇文章有一个相关的第一人称采访的第一作者的文件作为补充信息的一部分。
Epilepsy is a neurological disease that is caused by abnormal hypersynchronous activities of neuronal ensembles leading to recurrent and spontaneous seizures in human patients. Enhanced neuronal excitability and a high level of synchrony between neurons seem to trigger these spontaneous seizures. The molecular mechanisms, however, regarding the development of neuronal hyperexcitability and maintenance of epilepsy are still poorly understood. Here, we show that pumilio RNA-binding family member 2 (Pumilio2; Pum2) plays a role in the regulation of excitability in hippocampal neurons of weaned and 5-month-old male mice. Almost complete deficiency of Pum2 in adult Pum2 gene-trap mice (Pum2 GT) causes misregulation of genes involved in neuronal excitability control. Interestingly, this finding is accompanied by the development of spontaneous epileptic seizures in Pum2 GT mice. Furthermore, we detect an age-dependent increase in Scn1a (Nav1.1) and Scn8a (Nav1.6) mRNA levels together with a decrease in Scn2a (Nav1.2) transcript levels in weaned Pum2 GT that is absent in older mice. Moreover, field recordings of CA1 pyramidal neurons show a tendency towards a reduced paired-pulse inhibition after stimulation of the Schaffer-collateral-commissural pathway in Pum2 GT mice, indicating a predisposition to the development of spontaneous seizures at later stages. With the onset of spontaneous seizures at the age of 5 months, we detect increased protein levels of Nav1.1 and Nav1.2 as well as decreased protein levels of Nav1.6 in those mice. In addition, GABA receptor subunit alpha-2 (Gabra2) mRNA levels are increased in weaned and adult mice. Furthermore, we observe an enhanced GABRA2 protein level in the dendritic field of the CA1 subregion in the Pum2 GT hippocampus. We conclude that altered expression levels of known epileptic risk factors such as Nav1.1, Nav1.2, Nav1.6 and GABRA2 result in enhanced seizure susceptibility and manifestation of epilepsy in the hippocampus. Thus, our results argue for a role of Pum2 in epileptogenesis and the maintenance of epilepsy. Summary: Epileptogenic risk factors are misregulated in Pumilio2-deficient mice, determining a predisposition to develop seizures. This article has an associated First Person interview with the first author of the paper as part of the supplementary information.
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影响因子：
2.5
作者：
Schindelin J;Rueden CT;Hiner MC;Eliceiri KW
通讯作者：
Eliceiri KW
影响因子：
4.3
作者：
Lin WH;Giachello CN;Baines RA
通讯作者：
Baines RA
影响因子：
16.2
作者：
Gulledge, AT;Stuart, GJ
通讯作者：
Stuart, GJ
DOI：
10.3791/3564
发表时间：
2012-07-30
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Gage, Gregory J;Kipke, Daryl R;Shain, William
通讯作者：
Shain, William
影响因子：
2.4
作者：
Kohler, I;Meier, R;Schatzmann, U
通讯作者：
Schatzmann, U