June 7, 2019

When a Good Cop Turns Bad: The Pro-Seizure Action of Neurons that are Normally Anti-Seizure

Featuring the work of CURE Former Grantee Chris Dulla

Background: 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.

Methods: Here, researchers 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.

Results: This study shows that photo-depolarization of parvalbumin interneurons rapidly switches from an anti-ictal [anti-seizure] to a pro-ictal [pro-seizure] 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. The team also shows that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons.

Significance: 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.

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