KCC2 downregulation after sciatic nerve injury enhances motor function recovery.

Autor: Cheung DL; Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Aichi, Japan., Toda T; Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Aichi, Japan., Narushima M; Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Aichi, Japan., Eto K; Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.; Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan., Takayama C; University of the Ryukyus, Nishihara, Okinawa, Japan., Ooba T; Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Aichi, Japan., Wake H; Division of Multicellular Circuit Dynamics, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.; Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan., Moorhouse AJ; School of Biomedical Sciences, UNSW Sydney (The University of New South Wales), Sydney, New South Wales, Australia., Nabekura J; Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Aichi, Japan. nabekura@nips.ac.jp.; Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan. nabekura@nips.ac.jp.; School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan. nabekura@nips.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 May 15; Vol. 13 (1), pp. 7871. Date of Electronic Publication: 2023 May 15.
DOI: 10.1038/s41598-023-34701-y
Abstrakt: Injury to mature neurons induces downregulated KCC2 expression and activity, resulting in elevated intracellular [Cl - ] and depolarized GABAergic signaling. This phenotype mirrors immature neurons wherein GABA-evoked depolarizations facilitate neuronal circuit maturation. Thus, injury-induced KCC2 downregulation is broadly speculated to similarly facilitate neuronal circuit repair. We test this hypothesis in spinal cord motoneurons injured by sciatic nerve crush, using transgenic (CaMKII-KCC2) mice wherein conditional CaMKIIα promoter-KCC2 expression coupling selectively prevents injury-induced KCC2 downregulation. We demonstrate, via an accelerating rotarod assay, impaired motor function recovery in CaMKII-KCC2 mice relative to wild-type mice. Across both cohorts, we observe similar motoneuron survival and re-innervation rates, but differing post-injury reorganization patterns of synaptic input to motoneuron somas-for wild-type, both VGLUT1-positive (excitatory) and GAD67-positive (inhibitory) terminal counts decrease; for CaMKII-KCC2, only VGLUT1-positive terminal counts decrease. Finally, we recapitulate the impaired motor function recovery of CaMKII-KCC2 mice in wild-type mice by administering local spinal cord injections of bicuculline (GABA A receptor blockade) or bumetanide (lowers intracellular [Cl - ] by NKCC1 blockade) during the early post-injury period. Thus, our results provide direct evidence that injury-induced KCC2 downregulation enhances motor function recovery and suggest an underlying mechanism of depolarizing GABAergic signaling driving adaptive reconfiguration of presynaptic GABAergic input.
(© 2023. The Author(s).)
Databáze: MEDLINE
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