Approaches to control epilepsy, one of the most important idiopathic brain disorders, are of great importance for public health. We have previously shown that in sympathetic neurons the neuronal isoform of the serum and glucocorticoid-regulated kinase (SGK1.1) increases the M-current, a well-known target for seizure control. The effect of SGK1.1 activation on kainate-induced seizures and neuronal excitability was studied in transgenic mice that express a permanently active form of the kinase, using electroencephalogram recordings and electrophysiological measurements in hippocampal brain slices. Our results demonstrate that SGK1.1 activation leads to reduced seizure severity and lower mortality rates following status epilepticus, in an M-current-dependent manner. EEG is characterized by reduced number, shorter duration, and early termination of kainate-induced seizures in the hippocampus and cortex. Hippocampal neurons show decreased excitability associated to increased M-current, without altering basal synaptic transmission or other neuronal properties. Altogether, our results reveal a novel and selective anticonvulsant pathway that promptly terminates seizures, suggesting that SGK1.1 activation can be a potent factor to secure the brain against permanent neuronal damage associated to epilepsy.

译文

控制癫痫的方法是最重要的特发性脑部疾病之一,对公共卫生至关重要。我们以前已经表明,在交感神经元中,血清和糖皮质激素调节激酶 (SGK1.1) 的神经元同工型会增加M电流,这是控制癫痫发作的众所周知的靶标。在表达激酶永久活性形式的转基因小鼠中,使用脑电图记录和电生理测量在海马脑切片中研究了SGK1.1激活对海藻酸盐诱导的癫痫发作和神经元兴奋性的影响。我们的结果表明,SGK1.1激活以M电流依赖性方式导致癫痫持续状态后癫痫发作严重程度降低和死亡率降低。脑电图的特征是海马和皮层海藻酸盐诱发的癫痫发作的数量减少,持续时间缩短和提前终止。海马神经元表现出与M电流增加相关的兴奋性降低,而没有改变基底突触传递或其他神经元特性。总之,我们的结果揭示了一种新颖的选择性抗惊厥途径,可迅速终止癫痫发作,这表明SGK1.1激活可能是确保大脑免受与癫痫相关的永久性神经元损伤的有效因素。

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