NT-3 promotes functional recovery after spinal cord injury by bidirectionally regulating oligodendrocyte autophagy via P75NTR/TrkC receptor switching

Background Spinal cord injury (SCI) results in permanent functional deficits, and effective neurorehabilitative strategies remain an unmet clinical need. Neurotrophin-3 (NT-3) has emerged as a candidate therapeutic agent, but its molecular mechanisms in promoting functional recovery are incompletely understood. Methods A rat SCI model was established. Motor function recovery was assessed using the Basso-Beattie-Bresnahan (BBB) score, and related protein expression was detected via western blotting and immunofluorescence. In vitro , an oxygen–glucose deprivation (OGD) model in primary oligodendrocytes was used to simulate injury. Receptor knockdown, pathway inhibitors [3-methyladenine (3-MA), rapamycin (Rap)], a ubiquitination inhibitor (PYR41), and an endocytosis inhibitor (cytochalasin B), combined with co-immunoprecipitation, immunofluorescence, and western blot analysis, were employed to systematically investigate the temporal regulation of autophagy by NT-3, the involved signaling pathways (AMPK/mTOR and PI3K/AKT/mTOR), and the ubiquitination-dependent endocytic degradation of the P75 neurotrophin receptor (P75 NTR ). Results In vivo , endogenous NT-3 increased after SCI, and exogenous NT-3 significantly improved BBB scores at days 3 and 7, reduced oligodendrocyte apoptosis, and increased PLP1 expression at day 7. Mechanistically, NT-3 bidirectionally regulated autophagy: acute phase (day 3 in vivo /3 h in vitro ) via P75 NTR /AMPK/mTOR, and subacute phase (day 7 in vivo /12 h in vitro ) via TrkC/PI3K/AKT/mTOR. This receptor switch was driven by NT-3-induced ubiquitination-dependent endocytosis and degradation of P75 NTR . These molecular changes correlated with enhanced functional recovery and myelin repair. Conclusion NT-3 induces ubiquitination-dependent endocytic degradation of P75 NTR , enabling a temporal switch from P75 NTR /AMPK/mTOR to TrkC/PI3K/AKT/mTOR signaling, resulting in a fine-tuned, bidirectional regulation of oligodendrocyte autophagy after SCI. This dynamic regulation is a key mechanism by which NT-3 sustains oligodendrocyte survival, promotes myelin repair, and facilitates functional recovery.