Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus
Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus
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DOI：
10.1007/s00429-014-0798-5
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发表时间：
2015-07-01
影响因子：
3.1
通讯作者：
Henshall, David C.
中科院分区：
文献类型：
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作者：
Jimenez-Mateos, Eva M.;Engel, Tobias;Henshall, David C.
新的数据支持 microRNA (miRNA) 在包括癫痫在内的各种神经系统疾病的发病机制中的作用。 MicroRNA-134 (miR-134) 富含于海马神经元的树突中，它对脊柱体积有负调节作用。最近的研究发现 miR-134 在实验性癫痫和人类癫痫中上调。使用antagomir在体内靶向miR-134对红藻氨酸诱导的癫痫发作具有有效的抗惊厥作用，并且与树突棘数量的减少有关。在本研究中，我们测量了注射 miR-134 靶向 antagomir 的小鼠的树突棘体积，并测试了 antagomir 对胆碱能激动剂毛果芸香碱引发的癫痫持续状态的影响。对注射荧光黄的 CA3 锥体神经元中 6,400 多个树突棘的形态测量分析显示，与接受乱序序列的对照组相比，给予 antagomir 的小鼠的脊柱体积增加。用 miR-134 antagomir 治疗小鼠并没有改变行为测试（新物体定位）中的表现。毛果芸香碱诱导的癫痫持续状态与小鼠海马内 miR-134 的上调有关。用 miR-134 antagomir 预处理小鼠可降低毛果芸香碱后发生癫痫持续状态的动物比例，并提高动物存活率。在接受 antagomir 治疗的小鼠中，确实出现癫痫持续状态，癫痫发作延迟，总癫痫发作功率降低。这些研究提供了 miR-134 调节海马体脊柱体积的体内证据，并在具有不同触发机制的模型中验证了 miR-134 antagomir 的癫痫发作抑制作用，表明抗惊厥作用具有广泛的保守性。
Emerging data support roles for microRNA (miRNA) in the pathogenesis of various neurologic disorders including epilepsy. MicroRNA-134 (miR-134) is enriched in dendrites of hippocampal neurons, where it negatively regulates spine volume. Recent work identified upregulation of miR-134 in experimental and human epilepsy. Targeting miR-134 in vivo using antagomirs had potent anticonvulsant effects against kainic acid-induced seizures and was associated with a reduction in dendritic spine number. In the present study, we measured dendritic spine volume in mice injected with miR-134-targeting antagomirs and tested effects of the antagomirs on status epilepticus triggered by the cholinergic agonist pilocarpine. Morphometric analysis of over 6,400 dendritic spines in Lucifer yellow-injected CA3 pyramidal neurons revealed increased spine volume in mice given antagomirs compared to controls that received a scrambled sequence. Treatment of mice with miR-134 antagomirs did not alter performance in a behavioral test (novel object location). Status epilepticus induced by pilocarpine was associated with upregulation of miR-134 within the hippocampus of mice. Pretreatment of mice with miR-134 antagomirs reduced the proportion of animals that developed status epilepticus following pilocarpine and increased animal survival. In antagomir-treated mice that did develop status epilepticus, seizure onset was delayed and total seizure power was reduced. These studies provide in vivo evidence that miR-134 regulates spine volume in the hippocampus and validation of the seizure-suppressive effects of miR-134 antagomirs in a model with a different triggering mechanism, indicating broad conservation of anticonvulsant effects.