Role of KCC2-dependent potassium efflux in 4-Aminopyridine-induced Epileptiform synchronization

Neurobiol Dis. 2018 Jan;109(Pt A):137-147. doi: 10.1016/j.nbd.2017.10.011. Epub 2017 Oct 16.

Abstract

A balance between excitation and inhibition is necessary to maintain stable brain network dynamics. Traditionally, seizure activity is believed to arise from the breakdown of this delicate balance in favor of excitation with loss of inhibition. Surprisingly, recent experimental evidence suggests that this conventional view may be limited, and that inhibition plays a prominent role in the development of epileptiform synchronization. Here, we explored the role of the KCC2 co-transporter in the onset of inhibitory network-induced seizures. Our experiments in acute mouse brain slices, of either sex, revealed that optogenetic stimulation of either parvalbumin- or somatostatin-expressing interneurons induced ictal discharges in rodent entorhinal cortex during 4-aminopyridine application. These data point to a proconvulsive role of GABAA receptor signaling that is independent of the inhibitory input location (i.e., dendritic vs. somatic). We developed a biophysically realistic network model implementing dynamics of ion concentrations to explore the mechanisms leading to inhibitory network-induced seizures. In agreement with experimental results, we found that stimulation of the inhibitory interneurons induced seizure-like activity in a network with reduced potassium A-current. Our model predicts that interneuron stimulation triggered an increase of interneuron firing, which was accompanied by an increase in the intracellular chloride concentration and a subsequent KCC2-dependent gradual accumulation of the extracellular potassium promoting epileptiform ictal activity. When the KCC2 activity was reduced, stimulation of the interneurons was no longer able to induce ictal events. Overall, our study provides evidence for a proconvulsive role of GABAA receptor signaling that depends on the involvement of the KCC2 co-transporter.

Keywords: 4-aminopyridine; Epileptic seizures; Ion concentration dynamics; KCC2 co-transporter; Network models.

MeSH terms

  • 4-Aminopyridine / administration & dosage
  • Animals
  • Cortical Synchronization*
  • Entorhinal Cortex / metabolism
  • Entorhinal Cortex / physiopathology
  • Epilepsy / chemically induced
  • Epilepsy / metabolism
  • Epilepsy / physiopathology*
  • Female
  • Interneurons / metabolism
  • Interneurons / physiology*
  • Male
  • Mice
  • Neural Networks, Computer
  • Parvalbumins / metabolism
  • Potassium / metabolism*
  • Potassium Channel Blockers / administration & dosage
  • Receptors, GABA-A / physiology
  • Seizures / chemically induced
  • Seizures / metabolism
  • Seizures / physiopathology*
  • Somatostatin / metabolism
  • Symporters / metabolism
  • Symporters / physiology*

Substances

  • Parvalbumins
  • Potassium Channel Blockers
  • Receptors, GABA-A
  • Symporters
  • potassium-chloride symporters
  • Somatostatin
  • 4-Aminopyridine
  • Potassium