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The Journal of Neuroscience, June 1, 2002, 22(11):4412-4417
Reduction of KCC2 Expression and GABAA
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 GABAA
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 GABAA receptor-mediated response, presumably equal to the equilibrium potential of
Cl , were more depolarized than that in intact
neurons. Thus, GABAA 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+
Copyright © 2002 Society for Neuroscience 0270-6474/02/22114412-06$05.00/0
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