Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
Nat Commun. 2019 Mar 15;10(1):1225. doi: 10.1038/s41467-019-08933-4.
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.
尽管皮层中间神经元显然非常适合抑制癫痫发作，但最近有几项报告强调了胞体靶向的钙结合蛋白阳性（PV+）中间神经元在癫痫发生中的矛盾作用。在这里，我们使用清醒活动小鼠的急性局灶性皮质癫痫发作模型，以及对 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，在癫痫发作开始后的几秒钟内，PV+中间神经元的光去极化作用迅速从抗癫痫发作转变为致癫痫发作作用。PV+中间神经元的延迟光刺激的致癫痫发作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，通过在主要皮质神经元中过度表达神经元钾氯共转运蛋白 KCC2 可以防止这种转变。这些结果表明，旨在提高主要神经元在面对过度网络活动时维持跨膜氯离子梯度的能力的策略可以防止中间神经元促进癫痫发作的持续。
