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

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 Ca2+ concentration ([Ca2+](i)) dynamics in a rat facial-nerve-transection model. In facial motoneurons, an elevation of the resting [Ca2+](i), GABA-mediated [Ca2+](i) transients, enhancement of the glutamate-evoked [Ca2+](i) increases, and spontaneous [Ca2+](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 [Ca2+](i) oscillations via facilitation of NMDA-receptor activation. Such GABA(A)-receptor-mediated [Ca2+](i) oscillations may play a role in neural survival and regeneration.