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The Journal of Neuroscience, February 6, 2008, 28(6):1301-1312; doi:10.1523/JNEUROSCI.3378-07.2008

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Cellular/Molecular
Thermodynamic Regulation of NKCC1-Mediated Cl^– Cotransport Underlies Plasticity of GABA_A Signaling in Neonatal Neurons

Audrey C. Brumback¹ and Kevin J. Staley²

¹Neuroscience Program and Medical Scientist Training Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, and ²Departments of Neurology and Pediatrics, Massachusetts General Hospital, Boston, Massachusetts 02114

Correspondence should be addressed to Kevin J. Staley, Departments of Neurology and Pediatrics, Massachusetts General Hospital, Boston, MA 02114. Email: kstaley{at}partners.org

In the adult brain, chloride (Cl^–) influx through GABA_A receptors is an important mechanism of synaptic inhibition. However, under a variety of circumstances, including acquired epilepsy, neuropathic pain, after trains of action potentials or trauma, and during normal early brain development, GABA_A receptor activation excites neurons by gating Cl^– efflux because the intracellular Cl^– concentration (Cl_i) is elevated. These findings require an inducible, active mechanism of chloride accumulation. We used gramicidin-perforated patch recordings to characterize Cl^– transport via NKCC1, the principal neuronal Cl^– accumulator, in neonatal CA1 pyramidal neurons. NKCC1 activity was required to maintain elevated Cl_i such that GABA_A receptor activation was depolarizing. Kinetic analysis of NKCC1 revealed reversible transmembrane Cl^– transport characterized by a large maximum velocity (v_max) and high affinity (K_m), so that NKCC1 transport was limited only by the net electrochemical driving force for Na⁺, K⁺, and Cl^–. At the steady-state Cl_i, NKCC1 was at thermodynamic equilibrium, and there was no evidence of net Cl^– transport. Trains of action potentials that have been previously shown to induce persistent changes in neuronal E_Cl (reversal potential for Cl^–) did not alter v_max or K_m of NKCC1. Rather, action potentials shifted the thermodynamic set point, the steady-state Cl_i at which there was no net NKCC1-mediated Cl^– transport. The persistent increase in Cl_i required intact 2/3 Na⁺-K⁺-ATPase activity, indicating that trains of action potentials reset the thermodynamic equilibrium for NKCC1 transport by lowering Na_i. Activity-induced changes in Na⁺-K⁺-ATPase activity comprise a novel mechanism for persistent alterations in synaptic signaling mediated by GABA.

Key words: seizure; sodium pump; development; long-term potentiation; dendrite; action potential; gramicidin-perforated patch

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Received July 25, 2007; revised Nov. 30, 2007; accepted Dec. 1, 2007.

Correspondence should be addressed to Kevin J. Staley, Departments of Neurology and Pediatrics, Massachusetts General Hospital, Boston, MA 02114. Email: kstaley{at}partners.org

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