KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels

Cell Rep. 2019 Jul 2;28(1):91-103.e7. doi: 10.1016/j.celrep.2019.06.001.

Abstract

KCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents is depolarized in KCC2 knockdown neurons, this shift is compensated by depolarization of the resting membrane potential. This reflects downregulation of leak potassium currents. We show KCC2 interacts with Task-3 (KCNK9) channels and is required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that perturb network activity thus offering additional targets for therapeutic intervention.

Keywords: GABA; K2P; KCC2; chloride; dentate gyrus; epilepsy; hippocampus; leak channels; synaptic transmission; transporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / metabolism*
  • Evoked Potentials / genetics
  • Evoked Potentials / physiology
  • GABA Antagonists / pharmacology
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Potentials / genetics
  • Membrane Potentials / physiology
  • Neurons / metabolism*
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism*
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Rats
  • Rats, Wistar
  • Seizures / chemically induced
  • Seizures / genetics
  • Seizures / metabolism*
  • Symporters / genetics
  • Symporters / metabolism*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • GABA Antagonists
  • Kcnk9 protein, rat
  • Potassium Channels
  • Potassium Channels, Tandem Pore Domain
  • Symporters
  • potassium-chloride symporters
  • gamma-Aminobutyric Acid