Induction of NMDA and GABAAReceptor-Mediated Ca2+Oscillations With KCC2 mRNA Downregulation in Injured Facial Motoneurons

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Abstract
To clarify the changes that occur in γ-aminobutyric acid type A (GABAA) 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+]itransients, enhancement of the glutamate-evoked [Ca2+]i increases, and spontaneous [Ca2+]ioscillations were induced by axotomy. All these axotomy-induced modifications were abolished by the GABAA-receptor antagonist bicuculline andN-methyl-d-aspartate (NMDA)-receptor antagonistd(−)-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 GABAA-receptor-mediated [Ca2+]i oscillations may play a role in neural survival and regeneration.