Details

Autor(en) / Beteiligte

• Cheung, Dennis Lawrence
• Toda, Takuya
• Narushima, Madoka
• Eto, Kei
• Takayama, Chitoshi
• Ooba, Tatsuko
• Wake, Hiroaki
• Moorhouse, Andrew John
• Nabekura, Junichi

Titel

KCC2 downregulation after sciatic nerve injury enhances motor function recovery

Ist Teil von

• Scientific reports, 2023-05, Vol.13 (1), p.7871-7871, Article 7871

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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.