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

Junichi Nabekura, Tsuyoshi Ueno, Akihiko Okabe, Akiko Furuta, Toru Iwaki, Chigusa Shimizu-Okabe, Atsuo Fukuda, Norio Akaike

Research output: Contribution to journalArticlepeer-review

207 Citations (Scopus)

Abstract

After axotomy, application of muscimol, a GABAA receptor agonist, induced an increase in intracellular Ca2+ ([Ca 2+]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.

Original languageEnglish
Pages (from-to)4412-4417
Number of pages6
JournalJournal of Neuroscience
Volume22
Issue number11
DOIs
Publication statusPublished - Jun 1 2002

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Reduction of KCC2 Expression and GABA<sub>A</sub> Receptor-Mediated Excitation after In Vivo Axonal Injury'. Together they form a unique fingerprint.

Cite this