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In this study, we tested whether modulating the neuronal excitability by pharmacological potassium\u2013chloride cotransporter (KCC2) activation could enhance the functional outcomes of these regenerative treatments in a complete spinal cord injury (SCI) in adult rats. We found that while osteopontin\/insulin-like growth factor 1 overexpression (to enhance axon regeneration) or neural stem cell (NSC) transplantation (to build a relay) alone failed to restore the interrupted spinal circuitry, the double treatment facilitated the integration of NSCs into the host spinal network, significantly promoting axonal regeneration and synapse formation. Behavioral assessments demonstrated that the addition of CLP290, a KCC2 agonist, to the combined treatment markedly improved hindlimb locomotion, as evidenced by higher Basso, Beattie and Bresnahan (BBB) scores and enhanced joint oscillation in fine locomotion analysis. Consistently, electrophysiological evaluations indicated partial restoration of electrical transmission through the reconstructed spinal network. Our findings highlight the synergistic effects of KCC2-mediated neuronal modulation on promoting functional recovery after complete SCI.<\/jats:p>","DOI":"10.1073\/pnas.2421823122","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T20:03:37Z","timestamp":1765224217000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Functional recovery induced by KCC2-enabled relay pathways in completely injured spinal cords in adult rats"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5854-9352","authenticated-orcid":false,"given":"Yaxian","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University","place":["Nantong, People\u2019s Republic of China"]},{"name":"School of Nursing and Rehabilitation, Nantong 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