KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition

Vincent Magloire (), Jonathan Cornford, Andreas Lieb, Dimitri M. Kullmann and Ivan Pavlov ()
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Vincent Magloire: University College London
Jonathan Cornford: University College London
Andreas Lieb: University College London
Dimitri M. Kullmann: University College London
Ivan Pavlov: University College London

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08933-4

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