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Reduction of KCC2 expression and GABAA receptor-mediated excitation after in vivo axonal injury.

ABSTRACT: After axotomy, application of muscimol, a GABA(A) receptor agonist, induced an increase in intracellular Ca(2+) ([Ca(2+)](i)) in dorsal motor neurons of the vagus (DMV neurons). Elevation of [Ca(2+)](i) by muscimol was blocked by bicuculline, tetrodotoxin, and Ni(2+). 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.

SUBMITTER: Nabekura J

PROVIDER: S-EPMC6758784 | biostudies-literature | 2002 Jun

REPOSITORIES: biostudies-literature

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Reduction of KCC2 expression and GABAA receptor-mediated excitation after in vivo axonal injury.

Nabekura Junichi J Ueno Tsuyoshi T Okabe Akihiko A Furuta Akiko A Iwaki Toru T Shimizu-Okabe Chigusa C Fukuda Atsuo A Akaike Norio N

The Journal of neuroscience : the official journal of the Society for Neuroscience 20020601 11

After axotomy, application of muscimol, a GABA(A) receptor agonist, induced an increase in intracellular Ca(2+) ([Ca(2+)](i)) in dorsal motor neurons of the vagus (DMV neurons). Elevation of [Ca(2+)](i) by muscimol was blocked by bicuculline, tetrodotoxin, and Ni(2+). 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 ...[more]

PMID: 12040048

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Reduction of KCC2 expression and GABAA receptor-mediated excitation after in vivo axonal injury.

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Reduction of KCC2 expression and GABAA receptor-mediated excitation after in vivo axonal injury.

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