Chloride cotransporter KCC2 is essential for GABAergic inhibition in the SCN

Neuropharmacology. 2018 Aug;138:80-86. doi: 10.1016/j.neuropharm.2018.05.023. Epub 2018 May 18.


One of the principal neurotransmitters of the central nervous system is GABA. In the adult brain, GABA is predominantly inhibitory, but there is growing evidence indicating that GABA can shift to excitatory action depending on environmental conditions. In the mammalian central circadian clock of the suprachiasmatic nucleus (SCN) GABAergic activity shifts from inhibition to excitation when animals are exposed to long day photoperiod. The polarity of the GABAergic response (inhibitory versus excitatory) depends on the GABA equilibrium potential determined by the intracellular Cl- concentration ([Cl-]i). Chloride homeostasis can be regulated by Cl- cotransporters like NKCC1 and KCC2 in the membrane, but the mechanisms for maintaining [Cl-]i are still under debate. This study investigates the role of KCC2 on GABA-induced Ca2+ transients in SCN neurons from mice exposed to different photoperiods. We show for the first time that blocking KCC2 with the newly developed blocker ML077 can cause a shift in the polarity of the GABAergic response. This will increase the amount of excitatory responses in SCN neurons and thus cause a shift in excitatory/inhibitory ratio. These results indicate that KCC2 is an essential component in regulating [Cl-]i and the equilibrium potential of Cl- and thereby determining the sign of the GABAergic response. Moreover, our data suggest a role for the Cl- cotransporters in the switch from inhibition to excitation observed under long day photoperiod.

Keywords: Calcium; Circadian; Excitation/inhibition ratio; GABA; KCC2; ML077.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Central Nervous System Agents / pharmacology
  • Chlorides / metabolism
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology
  • Male
  • Mice, Inbred C57BL
  • Neural Inhibition / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Photoperiod
  • Pyridazines / pharmacology
  • Suprachiasmatic Nucleus / drug effects
  • Suprachiasmatic Nucleus / metabolism*
  • Symporters / antagonists & inhibitors
  • Symporters / metabolism*
  • Thiazoles / pharmacology
  • Tissue Culture Techniques
  • gamma-Aminobutyric Acid / metabolism*


  • Central Nervous System Agents
  • Chlorides
  • Pyridazines
  • Symporters
  • Thiazoles
  • VU0255011
  • potassium-chloride symporters
  • gamma-Aminobutyric Acid
  • Calcium