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The Journal of Neuroscience, June 20, 2007, 27(25):6751-6759; doi:10.1523/JNEUROSCI.1337-07.2007

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Cellular/Molecular
NKCC1 Phosphorylation Stimulates Neurite Growth of Injured Adult Sensory Neurons

Simon Pieraut,^1,2 Valérie Laurent-Matha,^1,2 Chamroeun Sar,¹ Thomas Hubert,¹ Ilana Méchaly,^1,2 Cécile Hilaire,³ Marcel Mersel,¹ Eric Delpire,⁴ Jean Valmier,^1,2 and Frédérique Scamps¹

¹Inserm, Unité 583, F-34000 Montpellier, France, ²Université Montpellier II, F-34000 Montpellier, France, ³Université Franche Comté, F-25000 Besançon, France, and ⁴Vanderbilt University, Nashville, Tennessee 37235

Correspondence should be addressed to Dr. Frédérique Scamps, Institut des Neurosciences de Montpellier–Hôpital St. Eloi, Inserm Unité 583, 80, rue Augustin Fliche, 34091 Montpellier Cedex 5, France. Email: scamps{at}univ-montp2.fr

Peripheral nerve section promotes regenerative, elongated neuritic growth of adult sensory neurons. Although the role of chloride homeostasis, through the regulation of ionotropic GABA receptors, in the growth status of immature neurons in the CNS begins to emerge, nothing is known of its role in the regenerative growth of injured adult neurons. To analyze the intracellular Cl^– variation after a sciatic nerve section in vivo, gramicidin perforated-patch recordings were used to study muscimol-induced currents in mice dorsal root ganglion neurons isolated from control and axotomized neurons. We show that the reversal potential of muscimol-induced current, E_GABA-A, was shifted toward depolarized potentials in axotomized neurons. This was attributable to Cl^– influx because removal of extracellular Cl^– prevented this shift. Application of bumetanide, an inhibitor of NKCC1 cotransporter and E_GABA-A recordings in sensory neurons from NKCC1^–/– mice, identified NKCC1 as being responsible for the increase in intracellular Cl^– in axotomized neurons. In addition, we demonstrate with a phospho-NKCC1 antibody that nerve injury induces an increase in the phosphorylated form of NKCC1 in dorsal root ganglia that could account for intracellular Cl^– accumulation. Time-lapse recordings of the neuritic growth of axotomized neurons show a faster growth velocity compared with control. Bumetanide, the intrathecal injection of NKCC1 small interfering RNA, and the use of NKCC1^–/– mice demonstrated that NKCC1 is involved in determining the velocity of elongated growth of axotomized neurons. Our results clearly show that NKCC1-induced increase in intracellular chloride concentration is a major event accompanying peripheral nerve regeneration.

Key words: NKCC1; phosphorylation; regenerative growth; injury; chloride homeostasis; DRG

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Received March 26, 2007; revised May 4, 2007; accepted May 7, 2007.

Correspondence should be addressed to Dr. Frédérique Scamps, Institut des Neurosciences de Montpellier–Hôpital St. Eloi, Inserm Unité 583, 80, rue Augustin Fliche, 34091 Montpellier Cedex 5, France. Email: scamps{at}univ-montp2.fr

This article has been cited by other articles:

				H. I. Rocha-Gonzalez, S. Mao, and F. J. Alvarez-Leefmans Na+,K+,2Cl- Cotransport and Intracellular Chloride Regulation in Rat Primary Sensory Neurons: Thermodynamic and Kinetic Aspects J Neurophysiol, July 1, 2008; 100(1): 169 - 184. [Abstract] [Full Text] [PDF]

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