NKCC1-dependent GABAergic excitation drives synaptic network maturation during early hippocampal development.
A high intracellular chloride concentration in immature neurons leads to a depolarizing action of GABA that is thought to shape the developing neuronal network. We show that GABA-triggered depolarization and Ca2+ transients were attenuated in mice deficient for the Na-K-2Cl cotransporter NKCC1. Correlated Ca2+ transients and giant depolarizing potentials (GDPs) were drastically reduced and the maturation of the glutamatergic and GABAergic transmission in CA1 delayed. Brain morphology, synaptic density, and expression levels of certain developmental marker genes were unchanged. The expression of lynx1, a protein known to dampen network activity, was decreased. In mice deficient for the neuronal Cl(-)/HCO(3)(-) exchanger AE3, GDPs were also diminished. These data show that NKCC1-mediated Cl(-) accumulation contributes to GABAergic excitation and network activity during early postnatal development and thus facilitates the maturation of excitatory and inhibitory synapses.
Pfeffer
Carsten K
CK
Max Delbrück Centrum für Molekulare Medizin (MDC) and Leibniz Institut für Molekulare Pharmakologie (FMP), D-13125 Berlin, Germany.
Stein
Valentin
V
Keating
Damien J
DJ
Maier
Hannes
H
Rinke
Ilka
I
Rudhard
York
Y
Hentschke
Moritz
M
Rune
Gabriele M
GM
Jentsch
Thomas J
TJ
Hübner
Christian A
CA
D000818:Animals; D000831:Animals, Newborn; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000254:growth & development*; D028021:Sodium-Potassium-Chloride Symporters / Q000172:deficiency / Q000502:physiology*; D064506:Solute Carrier Family 12, Member 2; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D005680:gamma-Aminobutyric Acid