Chloride cotransporter KCC2 is essential for GABAergic inhibition in the SCN

Neuropharmacology
A H O Olde EngberinkS Michel

Abstract

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...Continue Reading

Citations

Jan 24, 2020·Journal of Biological Rhythms·Jos H T Rohling, Janusz M Meylahn
Mar 13, 2020·Physiological Reviews·Jenna R M HarveyAndrea L Meredith
May 16, 2019·International Journal of Molecular Sciences·Sara HegaziHai-Ying Mary Cheng
Feb 1, 2021·Experimental Gerontology·Fabian-Xosé FernandezDavid C Negelspach
Dec 4, 2020·International Journal of Molecular Sciences·Katie AndrewsJinwei Zhang

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