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

Nat Commun. 2019 Mar 15;10(1):1225. doi: 10.1038/s41467-019-08933-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorides / metabolism
  • Disease Models, Animal
  • Electrocorticography
  • Electrodes
  • Female
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Humans
  • Interneurons / physiology*
  • Lentivirus / genetics
  • Male
  • Mice
  • Neocortex / cytology
  • Neocortex / physiology*
  • Neural Inhibition / physiology*
  • Neural Pathways / physiology
  • Optogenetics / instrumentation
  • Optogenetics / methods
  • Parvalbumins / metabolism
  • Patch-Clamp Techniques
  • Photic Stimulation
  • Seizures / diagnosis
  • Seizures / physiopathology*
  • Somatostatin / metabolism
  • Symporters / genetics
  • Symporters / metabolism*

Substances

  • Chlorides
  • Parvalbumins
  • Symporters
  • potassium-chloride symporters
  • Somatostatin