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The Journal of Neuroscience, June 1, 2002, 22(11):4412-4417

Reduction of KCC2 Expression and GABA_A Receptor-Mediated Excitation after In Vivo Axonal Injury

Junichi Nabekura¹, Tsuyoshi Ueno¹, Akihiko Okabe², Akiko Furuta³, Toru Iwaki³, Chigusa Shimizu-Okabe², Atsuo Fukuda², and Norio Akaike¹

¹ Department of Cellular and System Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan, ² Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan, and ³ Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

After axotomy, application of muscimol, a GABA_A receptor agonist, induced an increase in intracellular Ca²⁺ ([Ca²⁺]_i) in dorsal motor neurons of the vagus (DMV neurons). Elevation of [Ca²⁺]_i by muscimol was blocked by bicuculline, tetrodotoxin, and Ni²⁺. In axotomized DMV neurons measured with gramicidin perforated-patch recordings, reversal potentials of the GABA_A receptor-mediated response, presumably equal to the equilibrium potential of Cl, were more depolarized than that in intact neurons. Thus, GABA_A receptor-mediated excitation is suggested to be attributable to Cl efflux out of the cell because of increased intracellular Cl concentration ([Cl]_i) in axotomized neurons. Regulation of [Cl]_i in both control and injured neurons was disturbed by furosemide and bumetanide and by manipulating cation balance across the membrane, suggesting that functional alteration of furosemide-sensitive cation-Cl cotransporters is responsible for the increase of [Cl]_i after axotomy. In situ hybridization revealed that neuron-specific K⁺-Cl cotransporter (KCC2) mRNA was significantly reduced in the DMV after axotomy compared with that in control neurons. Similar expression of Na⁺, K⁺-Cl cotransporter mRNA was observed between axotomized and control DMV neurons. Thus, axotomy led to disruption of [Cl]_i regulation attributable to a decrease of KCC2 expression, elevation of intracellular Cl, and an excitatory response to GABA. A switch of GABA action from inhibitory to excitatory might be a mechanism contributing to excitotoxicity in injured neurons.

Key words: axotomy; GABA; excitation; motoneuron; NKCC1; Cl; Ca²⁺

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22114412-06$05.00/0

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