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The Journal of Neuroscience, October 15, 2000, 20(20):7531-7538

Abnormal GABA_A Receptor-Mediated Currents in Dorsal Root Ganglion Neurons Isolated from Na-K-2Cl Cotransporter Null Mice

Ki-Wug Sung^{1, 3}, Michael Kirby², Michael P. McDonald², David M. Lovinger^{1, 2, 3}, and Eric Delpire^{1, 3}

Departments of ¹ Anesthesiology, ² Pharmacology, and ³ Molecular Physiology and Biophysics, Center for Molecular Neuroscience and Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee 37232

We have recently disrupted Slc12a2, the gene encoding the secretory Na-K-2Cl cotransporter in mice (NKCC1) (Delpire et al., 1999). Gramicidin perforated-patch and whole-cell recordings were performed to study GABA-induced currents in dorsal root ganglion (DRG) neurons isolated from wild-type and homozygote NKCC1 knock-out mice. In wild-type DRG neurons, strong GABA-evoked inward current was observed at the resting membrane potential, suggesting active accumulation of Cl in these cells. This GABA-induced current was blocked by picrotoxin, a GABA_A receptor blocker. The strong Cl accumulation that gives rise to depolarizing GABA responses is caused by Na-K-2Cl cotransport because reduction of external Cl or application of bumetanide induced a decrease in [Cl]_i, whereas an increase in external K⁺ caused an apparent [Cl]_i accumulation. In contrast to control neurons, little or no net current was observed at the resting membrane potential in homozygote NKCC1 mutant DRG neurons. E_GABA was significantly more negative, demonstrating the absence of Cl accumulation in these cells. Application of bumetanide induced a positive shift of E_GABA, suggesting the presence of an outward Cl transport mechanism. In agreement with an absence of GABA depolarization in DRG neurons, behavioral analysis revealed significant alterations in locomotion and pain perception in the knock-out mouse. Our results clearly demonstrate that the Na-K-2Cl cotransporter is responsible for [Cl]_i accumulation in DRG neurons and that via regulation of intracellular Cl, the Na-K-2Cl cotransporter participates in the modulation of GABA neurotransmission and sensory perception.

Key words: Na-K-2Cl cotransporter; knock-out mouse; dorsal root ganglion; bumetanide; chloride; GABA; nociception

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20207531-08$05.00/0

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