Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish.
Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish.
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镶嵌和非镶嵌原钙粘蛋白19突变导致斑马鱼神经元过度兴奋。
DOI：
10.1016/j.nbd.2022.105738
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发表时间：
2022-07
影响因子：
6.1
通讯作者：
Poduri, Annapurna
中科院分区：
文献类型：
--
作者：
Robens, Barbara K.;Yang, Xinzhu;McGraw, Christopher M.;Turner, Laura H.;Robens, Carsten;Thyme, Summer;Rotenberg, Alexander;Poduri, Annapurna
关键词：
癫痫是最常见的神经系统疾病之一。 X连锁基因PCDH19与人类散发性和家族性癫痫有关，通常与女性早发的丛集性癫痫发作和智力障碍有关，但在所谓的“携带者”男性中则不然，这表明马赛克PCDH19表达是产生癫痫所必需的。为了表征 PCDH19 功能丧失在癫痫中的作用，我们培育了具有截短 pcdh19 变体的斑马鱼。在评估斑马鱼幼虫的电生理异常时，我们观察到嵌合和非嵌合 pcdh19+/- 和 pcdh19−/− 突变幼虫的过度兴奋表型。因此，我们证明癫痫的关键特征——网络过度兴奋——可以在斑马鱼中有效地建模，尽管没有观察到明显的自发癫痫样游泳模式。此外，具有非马赛克 pcdh19 突变的斑马鱼表现出抑制性中间神经元数量减少，这表明观察到的过度兴奋性具有潜在的细胞基础。我们在嵌合和非嵌合 PCDH19 突变斑马鱼中的发现挑战了嵌合现象控制所有 PCDH19 相关表型的流行理论，并指出了这些表型背后的中间神经元介导机制。
Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called ‘carrier’ males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/− and pcdh19−/− mutant larvae. Thus, we demonstrate that the key feature of epilepsy—network hyperexcitability—can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.
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影响因子：
11
作者：
Kolc KL;Sadleir LG;Scheffer IE;Ivancevic A;Roberts R;Pham DH;Gecz J
通讯作者：
Gecz J
影响因子：
3.7
作者：
Grone BP;Marchese M;Hamling KR;Kumar MG;Krasniak CS;Sicca F;Santorelli FM;Patel M;Baraban SC
通讯作者：
Baraban SC
影响因子：
4
作者：
Dentici, Maria Lisa;Alesi, Viola;Novelli, Antonio
通讯作者：
Novelli, Antonio
影响因子：
14.5
作者：
Griffin, Aliesha;Hamling, Kyla R.;Baraban, Scott C.
通讯作者：
Baraban, Scott C.
DOI：
10.1083/jcb.201507108
发表时间：
2015-11-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cooper SR;Emond MR;Duy PQ;Liebau BG;Wolman MA;Jontes JD
通讯作者：
Jontes JD