{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T05:47:54Z","timestamp":1792129674770,"version":"4.4.0"},"reference-count":61,"publisher":"Society for Neuroscience","issue":"6","license":[{"start":{"date-parts":[[2008,8,6]],"date-time":"2008-08-06T00:00:00Z","timestamp":1217980800000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2008,2,6]]},"abstract":"<jats:p>In the adult brain, chloride (Cl<jats:sup>\u2212<\/jats:sup>) influx through GABA<jats:sub>A<\/jats:sub>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<jats:sub>A<\/jats:sub>receptor activation excites neurons by gating Cl<jats:sup>\u2212<\/jats:sup>efflux because the intracellular Cl<jats:sup>\u2212<\/jats:sup>concentration (Cl<jats:sub>i<\/jats:sub>) is elevated. These findings require an inducible, active mechanism of chloride accumulation. We used gramicidin-perforated patch recordings to characterize Cl<jats:sup>\u2212<\/jats:sup>transport via NKCC1, the principal neuronal Cl<jats:sup>\u2212<\/jats:sup>accumulator, in neonatal CA1 pyramidal neurons. NKCC1 activity was required to maintain elevated Cl<jats:sub>i<\/jats:sub>such that GABA<jats:sub>A<\/jats:sub>receptor activation was depolarizing. Kinetic analysis of NKCC1 revealed reversible transmembrane Cl<jats:sup>\u2212<\/jats:sup>transport characterized by a large maximum velocity (<jats:italic>v<\/jats:italic><jats:sub>max<\/jats:sub>) and high affinity (<jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>), so that NKCC1 transport was limited only by the net electrochemical driving force for Na<jats:sup>+<\/jats:sup>, K<jats:sup>+<\/jats:sup>, and Cl<jats:sup>\u2212<\/jats:sup>. At the steady-state Cl<jats:sub>i<\/jats:sub>, NKCC1 was at thermodynamic equilibrium, and there was no evidence of net Cl<jats:sup>\u2212<\/jats:sup>transport. Trains of action potentials that have been previously shown to induce persistent changes in neuronal<jats:italic>E<\/jats:italic><jats:sub>Cl<\/jats:sub>(reversal potential for Cl<jats:sup>\u2212<\/jats:sup>) did not alter<jats:italic>v<\/jats:italic><jats:sub>max<\/jats:sub>or<jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>of NKCC1. Rather, action potentials shifted the thermodynamic set point, the steady-state Cl<jats:sub>i<\/jats:sub>at which there was no net NKCC1-mediated Cl<jats:sup>\u2212<\/jats:sup>transport. The persistent increase in Cl<jats:sub>i<\/jats:sub>required intact \u03b12\/\u03b13 Na<jats:sup>+<\/jats:sup>-K<jats:sup>+<\/jats:sup>-ATPase activity, indicating that trains of action potentials reset the thermodynamic equilibrium for NKCC1 transport by lowering Na<jats:sub>i<\/jats:sub>. Activity-induced changes in Na<jats:sup>+<\/jats:sup>-K<jats:sup>+<\/jats:sup>-ATPase activity comprise a novel mechanism for persistent alterations in synaptic signaling mediated by GABA.<\/jats:p>","DOI":"10.1523\/jneurosci.3378-07.2008","type":"journal-article","created":{"date-parts":[[2008,2,6]],"date-time":"2008-02-06T17:27:56Z","timestamp":1202318876000},"page":"1301-1312","source":"Crossref","is-referenced-by-count":100,"title":["Thermodynamic Regulation of NKCC1-Mediated Cl<sup>\u2212<\/sup>Cotransport Underlies Plasticity of GABA<sub>A<\/sub>Signaling in Neonatal Neurons"],"prefix":"10.1523","volume":"28","author":[{"given":"Audrey C.","family":"Brumback","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin 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