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 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.
Toyoda
Hiroki
H
Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
Ohno
Koji
K
Yamada
Junko
J
Ikeda
Masahiko
M
Okabe
Akihito
A
Sato
Kohji
K
Hashimoto
Kenji
K
Fukuda
Atsuo
A
D000818:Animals; D019771:Axotomy; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D005154:Facial Nerve / Q000166:cytology / Q000502:physiology; D020220:Facial Nerve Injuries / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology; D008297:Male; D009046:Motor Neurons / Q000502:physiology; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D000096922:K Cl- Cotransporters
D002118:Calcium; D002712:Chlorides; D018698:Glutamic Acid; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters