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The Journal of Neuroscience, March 18, 2009, 29(11):3419-3430; doi:10.1523/JNEUROSCI.1377-08.2009

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Development/Plasticity/Repair
NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development

Carsten K. Pfeffer,^1,2 Valentin Stein,³ Damien J. Keating,² Hannes Maier,⁴ Ilka Rinke,³ York Rudhard,² Moritz Hentschke,⁵ Gabriele M. Rune,⁶ Thomas J. Jentsch,^1,2 and Christian A. Hübner^2,5,7

¹Max Delbrück Centrum für Molekulare Medizin (MDC) and Leibniz Institut für Molekulare Pharmakologie (FMP), D-13125 Berlin, Germany, ²Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Universität Hamburg, D-20251 Hamburg, Germany, ³Max Planck Institut für Neurobiologie, D-82152 Martinsried, Germany, and ⁴Klinik für Hals-, Nasen- und Ohrenheilkunde, ⁵Institut für Humangenetik, ⁶Institut für Anatomie, Universitätsklinikum Hamburg-Eppendorf, D-22529 Hamburg, Germany, and ⁷Institut für Klinische Chemie, Friedrich Schiller Universität Jena, D-07747 Jena, Germany

Correspondence should be addressed to either of the following: Thomas J. Jentsch, MDC/FMP, Robert-Rössle-Strasse 10, D-13125 Berlin, Germany, Email: jentsch{at}fmp-berlin.de; or Christian A. Hübner, Institut für Klinische Chemie, Friedrich-Schiller-Universität Jena, Erlanger Allee 101, D-07747 Jena, Germany, Email: christian.huebner{at}med.uni-jena.de

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 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.

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Received April 1, 2008; revised Jan. 28, 2009; accepted Feb. 4, 2009.

Correspondence should be addressed to either of the following: Thomas J. Jentsch, MDC/FMP, Robert-Rössle-Strasse 10, D-13125 Berlin, Germany, Email: jentsch{at}fmp-berlin.de; or Christian A. Hübner, Institut für Klinische Chemie, Friedrich-Schiller-Universität Jena, Erlanger Allee 101, D-07747 Jena, Germany, Email: christian.huebner{at}med.uni-jena.de

This article has been cited by other articles:

				R. Wright The Necessity of NKCC1: Loss of the Chloride Cotransporter in a Knock-Out Model and Potential Compensatory Mechanisms J. Neurosci., October 21, 2009; 29(42): 13094 - 13096. [Full Text] [PDF]

				A. A. Zdebik, P. Wangemann, and T. J. Jentsch Potassium Ion Movement in the Inner Ear: Insights from Genetic Disease and Mouse Models Physiology, October 1, 2009; 24(5): 307 - 316. [Abstract] [Full Text] [PDF]

				S. T. Sipila, K. Huttu, J. Yamada, R. Afzalov, J. Voipio, P. Blaesse, and K. Kaila Compensatory Enhancement of Intrinsic Spiking upon NKCC1 Disruption in Neonatal Hippocampus J. Neurosci., May 27, 2009; 29(21): 6982 - 6988. [Abstract] [Full Text] [PDF]

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