KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition
KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition
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DOI：
10.1038/s41467-019-08933-4
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发表时间：
2019-03-15
影响因子：
16.6
通讯作者：
Pavlov, Ivan
中科院分区：
文献类型：
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作者：
Magloire, Vincent;Cornford, Jonathan;Pavlov, Ivan
虽然皮层中间神经元明显处于抑制癫痫发作的良好位置，但最近的一些报道强调了周围靶向小蛋白阳性（PV+）中间神经元在ictogenesis中的矛盾作用。在这里，我们使用清醒行为小鼠局灶性皮质癫痫的急性体内模型，以及PV+中间神经元的闭环光遗传学操作，来研究它们在癫痫发作期间的功能。我们发现PV+中间神经元的光去极化在癫痫发作开始的几秒钟内迅速从抗癫痫转变为促癫痫。延迟光刺激PV+中间神经元的促进作用与树突靶向生长抑素阳性（SOM+）中间神经元不同。我们还表明，这种开关可以通过主要皮质神经元中神经元氯化钾共转运体KCC2的过度表达来阻止。这些结果表明，旨在提高主神经元在面对过度网络活动时维持跨膜氯梯度的能力的策略可以防止中间神经元导致癫痫发作的持续。
Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of perisomatic-targeting parvalbumin-positive (PV+)interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain a trans-membrane chloride gradient in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.