Induction of NMDA and GABAA receptor-mediated Ca2+ oscillations with KCC2 mRNA downregulation in injured facial motoneurons

J Neurophysiol. 2003 Mar;89(3):1353-62. doi: 10.1152/jn.00721.2002. Epub 2002 Nov 13.

Abstract

To clarify the changes that occur in gamma-aminobutyric acid type A (GABA(A)) receptor-mediated effects and contribute to alterations in the network activities after neuronal injury, we studied intracellular Ca(2+) concentration ([Ca(2+)](i)) dynamics in a rat facial-nerve-transection model. In facial motoneurons, an elevation of the resting [Ca(2+)](i), GABA-mediated [Ca(2+)](i) transients, enhancement of the glutamate-evoked [Ca(2+)](i) increases, and spontaneous [Ca(2+)](i) oscillations were induced by axotomy. All these axotomy-induced modifications were abolished by the GABA(A)-receptor antagonist bicuculline and N-methyl-d-aspartate (NMDA)-receptor antagonist d(-)-2-amino-5-phosphonopentanoic acid. A downregulation of K(+)-Cl(-) cotransporter (KCC2) mRNA, an increase in intracellular Cl(-) concentration ([Cl(-)](i)), and transformation of GABAergic hyperpolarization to depolarization were also induced by axotomy. We suggest that in axotomized neurons KCC2 downregulation impairs Cl(-) homeostasis and makes GABA act depolarizing, resulting in endogenous GABA inducing [Ca(2+)](i) oscillations via facilitation of NMDA-receptor activation. Such GABA(A)-receptor-mediated [Ca(2+)](i) oscillations may play a role in neural survival and regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axotomy
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Chlorides / metabolism
  • Down-Regulation / physiology
  • Facial Nerve / cytology
  • Facial Nerve / physiology
  • Facial Nerve Injuries / physiopathology*
  • Gene Expression / physiology
  • Glutamic Acid / pharmacology
  • K Cl- Cotransporters
  • Male
  • Motor Neurons / physiology
  • Organ Culture Techniques
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / physiology*
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Symporters / genetics*
  • Symporters / metabolism
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Chlorides
  • RNA, Messenger
  • Receptors, GABA-A
  • Receptors, N-Methyl-D-Aspartate
  • Symporters
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Calcium