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首页> 外文期刊>Neuroscience: An International Journal under the Editorial Direction of IBRO >INCREASED SENSITIVITY TO KINDLING IN MICE LACKING TSP1
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INCREASED SENSITIVITY TO KINDLING IN MICE LACKING TSP1

机译：缺少TSP1的小鼠对幼稚的敏感性增加

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The development of a hyperexcitable neuronal network is thought to be a critical event in epilepsy. Thrombospondins (TSPs) regulate synaptogenesis by binding the neuronal alpha 2 delta subunit of the voltage-gated calcium channel. TSPs regulate synapse formation during development and in the mature brain following injury. It is unclear if TSPs are involved in hyperexcitability that contributes to the development of epilepsy. Here we explore the development of epilepsy using a pentylenetetrazole (PTZ) kindling model in mice lacking TSP1 and TSP2. Unexpectedly, we found increased sensitivity to PTZ kindling in mice lacking TSP1, while mice lacking TSP2 kindled similar to wild-type. We found that the increased seizure susceptibility in the TSP1 knockout (KO) mice was not due to a compensatory increase in TSP2 mRNA as TSP1/2 KO mice were sensitive to PTZ, similar to the TSP1 KO mice. Furthermore, there were similar levels of TGF-B signal activation during kindling in the TSP1 KO mice compared to wild-type. We observed decreased expression of voltage-dependent calcium channel subunit CACNA2D1 mRNA in TSP1, TSP2, and TSP1/2 KO mice. Decreased CACNA2D2 mRNA was only detected in mice that lacked TSP1 and alpha 2 delta-1/2 protein levels in the cortex were lower in the TSP 1/2 KO mice. CACNA2D2 knockout mice have spontaneous seizures and increased PTZ seizure susceptibility. Here we report similar findings, TSP1, and TSP1/2 KO mice have low levels of CACNA2D2 mRNA expression and alpha 2 delta-1/2 receptor level in the cortex, and are more susceptible to seizures. CACNA2D2 mutations in mice and humans can cause epilepsy. Our data suggest TSP1 in particular may control CACNA2D2 levels and could be a modifier of seizure susceptibility. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
机译：高兴奋性神经元网络的发展被认为是癫痫中的关键事件。血小板反应蛋白（TSP）通过结合电压门控钙通道的神经元α2δ亚基来调节突触发生。 TSPs在发育过程中和损伤后的成熟大脑中调节突触的形成。目前尚不清楚TSP是否参与导致癫痫发展的过度兴奋。在这里，我们探讨了在缺少TSP1和TSP2的小鼠中使用戊四氮（PTZ）点燃模型开发癫痫的方法。出乎意料的是，我们发现缺乏TSP1的小鼠对PTZ点燃的敏感性增加，而缺乏TSP2的小鼠与野生型相似。我们发现，与TSP1 KO小鼠类似，TSP1 / 2 KO小鼠对PTZ敏感，因此TSP1基因敲除（KO）小鼠的癫痫易感性增加不是由于TSP2 mRNA的代偿性增加。此外，与野生型相比，TSP1 KO小鼠在点燃过程中的TGF-B信号激活水平相似。我们观察到在TSP1，TSP2和TSP1 / 2 KO小鼠中电压依赖性钙通道亚基CACNA2D1 mRNA的表达降低。仅在缺乏TSP1的小鼠中检测到CACNA2D2 mRNA降低，而在TSP 1/2 KO小鼠的皮质中，α2delta-1 / 2蛋白水平较低。 CACNA2D2基因敲除小鼠具有自发性癫痫发作和PTZ癫痫发作易感性增加。在这里我们报告了类似的发现，TSP1和TSP1 / 2 KO小鼠的皮层中CACNA2D2 mRNA表达水平较低，α2delta-1 / 2受体水平较低，并且更容易发作。小鼠和人类中的CACNA2D2突变可引起癫痫病。我们的数据表明，TSP1尤其可以控制CACNA2D2的水平，并且可能是癫痫发作易感性的调节剂。 （C）2015年IBRO。由Elsevier Ltd.出版。保留所有权利。

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