Deletion of KCNQ2/3 potassium channels from PV+ interneurons leads to homeostatic potentiation of excitatory transmission.

Heun Soh,Kristen Springer,Suhyeorn Park,Kali Ryan,Atul Maheshwari,Anastasios V Tzingounis

doi:10.7554/elife.38617

Abstract

KCNQ2/3 channels, ubiquitously expressed neuronal potassium channels, have emerged as indispensable regulators of brain network activity. Despite their critical role in brain homeostasis, the mechanisms by which KCNQ2/3 dysfunction lead to hypersychrony are not fully known. Here, we show that deletion of KCNQ2/3 channels changed PV+ interneurons', but not SST+ interneurons', firing properties. We also find that deletion of either KCNQ2/3 or KCNQ2 channels from PV+ interneurons led to elevated homeostatic potentiation of fast excitatory transmission in pyramidal neurons. Pvalb-Kcnq2 null-mice showed increased seizure susceptibility, suggesting that decreases in interneuron KCNQ2/3 activity remodels excitatory networks, providing a new function for these channels.

Highlights

Genetic studies have established that potassium channel dysfunction is responsible for multiple pediatric epilepsy disorders (Brenner and Wilcox, 2012; Geisheker et al, 2017; Niday and Tzingounis, 2018; Oyrer et al, 2018)
We first examined whether ablation of KCNQ2/3 channels from interneurons led to changes in the excitatory and inhibitory drive of CA1 pyramidal neurons
We first focused our analysis on the second week of life, as KCNQ2/3 dysfunction is primarily associated with neonatal epilepsy (Oyrer et al, 2018)

Summary

Introduction

Genetic studies have established that potassium channel dysfunction is responsible for multiple pediatric epilepsy disorders (Brenner and Wilcox, 2012; Geisheker et al, 2017; Niday and Tzingounis, 2018; Oyrer et al, 2018). This gap in knowledge is partly because KCNQ2/3 function is most observed in neurons that undergo pronounced spike frequency adaptation, a characteristic not traditionally found in interneurons (Pelkey et al, 2017) It is currently unknown whether loss of KCNQ2/3 function in interneurons would have effects on overall network activity, and if it does, whether it would lead to a dampening or an increase in excitability. Previous work found that neonatal administration of bumetanide, which changes GABA receptor activity from depolarizating to hyperpolarizing, prevents seizures in mice with a global loss of KCNQ2 channels (Marguet et al, 2015) This may be evidence that loss of KCNQ2/3 function at this time increases network excitability through changes in interneuron GABA signaling, but the authors did not directly examine synaptic activity. We find that interneuronal loss of KCNQ2/3 or KCNQ2 channels increases excitatory transmission between pyramidal neurons, perhaps as homeostatic compensation for the increased GABAergic signaling we observe

Results and discussion

Materials and methods

Ethics statement