KCC2 downregulation after sciatic nerve injury enhances motor function recovery
Abstract 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-induce...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-34701-y |
| _version_ | 1797822897572544512 |
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| author | Dennis Lawrence Cheung Takuya Toda Madoka Narushima Kei Eto Chitoshi Takayama Tatsuko Ooba Hiroaki Wake Andrew John Moorhouse Junichi Nabekura |
| author_facet | Dennis Lawrence Cheung Takuya Toda Madoka Narushima Kei Eto Chitoshi Takayama Tatsuko Ooba Hiroaki Wake Andrew John Moorhouse Junichi Nabekura |
| author_sort | Dennis Lawrence Cheung |
| collection | DOAJ |
| description | Abstract 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 (GABAA 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. |
| first_indexed | 2024-03-13T10:16:00Z |
| format | Article |
| id | doaj.art-a84d0a83f5ea4143ab39f19a7adf745c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-13T10:16:00Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a84d0a83f5ea4143ab39f19a7adf745c2023-05-21T11:15:46ZengNature PortfolioScientific Reports2045-23222023-05-0113111910.1038/s41598-023-34701-yKCC2 downregulation after sciatic nerve injury enhances motor function recoveryDennis Lawrence Cheung0Takuya Toda1Madoka Narushima2Kei Eto3Chitoshi Takayama4Tatsuko Ooba5Hiroaki Wake6Andrew John Moorhouse7Junichi Nabekura8Division of Homeostatic Development, National Institute for Physiological SciencesDivision of Homeostatic Development, National Institute for Physiological SciencesDivision of Homeostatic Development, National Institute for Physiological SciencesDivision of Homeostatic Development, National Institute for Physiological SciencesUniversity of the RyukyusDivision of Homeostatic Development, National Institute for Physiological SciencesDivision of Multicellular Circuit Dynamics, National Institute for Physiological SciencesSchool of Biomedical Sciences, UNSW Sydney (The University of New South Wales)Division of Homeostatic Development, National Institute for Physiological SciencesAbstract 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 (GABAA 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.https://doi.org/10.1038/s41598-023-34701-y |
| spellingShingle | Dennis Lawrence Cheung Takuya Toda Madoka Narushima Kei Eto Chitoshi Takayama Tatsuko Ooba Hiroaki Wake Andrew John Moorhouse Junichi Nabekura KCC2 downregulation after sciatic nerve injury enhances motor function recovery Scientific Reports |
| title | KCC2 downregulation after sciatic nerve injury enhances motor function recovery |
| title_full | KCC2 downregulation after sciatic nerve injury enhances motor function recovery |
| title_fullStr | KCC2 downregulation after sciatic nerve injury enhances motor function recovery |
| title_full_unstemmed | KCC2 downregulation after sciatic nerve injury enhances motor function recovery |
| title_short | KCC2 downregulation after sciatic nerve injury enhances motor function recovery |
| title_sort | kcc2 downregulation after sciatic nerve injury enhances motor function recovery |
| url | https://doi.org/10.1038/s41598-023-34701-y |
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