Abstract: BACKGROUND: Neurotrophins represent a novel therapeutic approach for spinal cord injury, showing promising clinical applicability. Autophagy modulation is one of the mechanisms by which neurotrophins exert their effects, yet the specific signaling pathways involved remain unclear. 
OBJECTIVE: To explore how neurotrophin-3 (NT-3) modulates autophagy in oligodendrocytes via switching between P75NTR and TrkC receptors and promotes neurological function recovery after spinal cord injury, aiming to further clarify the specific molecular mechanisms involved.
METHODS: Twenty-four Sprague-Dawley rats were randomly divided into three groups: sham operation, spinal cord injury, and NT-3 groups. The therapeutic effect of NT-3 on spinal cord injury in rats was evaluated using the Basso, Beattie, and Bresnahan locomotor rating scale. The expression levels of NT-3, Olig1, myelin basic protein, and the autophagy marker LC3B in rat spinal cord tissue were detected by western blot. In a cellular experiment, oligodendrocytes were cultured in vitro and divided into six groups: oxygen-glucose deprivation (OGD), OGD+NT-3, OGD+NT-3+P75NTR plasmid, OGD+NT-3+TrkC plasmid, OGD+3-methyladenine (an autophagy inhibitor), and OGD+rapamycin (an autophagy activator). Oligodendrocyte morphology was observed under a light microscope, cell apoptosis was assessed by TUNEL staining, and the expression of TrkC receptor, P75NTR, LC3B, and the phosphorylation status of the PI3K/AKT/mTOR and AMPK/mTOR signaling pathways were evaluated by western blot.
RESULTS AND CONCLUSION: Animal experiments demonstrated that compared with the sham operation group, NT-3 expression significantly increased after spinal cord injury (P < 0.05); exogenous NT-3 treatment accelerated neurological function recovery in rats post spinal cord injury (P < 0.05) and increased the expression of Olig1 and myelin basic proteins (P < 0.05). Cellular experiments revealed that 3 hours marked the early to middle/late phase transition. Compared with the OGD group, oligodendrocytes in the OGD+NT-3 group could maintain their morphology for a longer period of time, TrkC receptor expression was lower in the early phase and significantly upregulated in the middle/late phase (P < 0.05), whereas P75NTR protein expression was upregulated in the early phase and downregulated in the middle/late phase (P < 0.05), and autophagy levels showed an initial increase followed by a decrease (P < 0.05). By comparing the morphology and TUNEL staining results of cells in the OGD+NT-3, OGD+rapamycin, and OGD+3-methyladenine groups, we found that either promoting or inhibiting autophagy alone had adverse effects on oligodendrocyte survival, whereas modulating autophagy in a manner similar to NT-3 could maximally maintain cell survival. NT-3 could promote autophagy in the early phase via the P75NTR/AMPK/mTOR signaling pathway and inhibit autophagy in the later phase through the TrkC/PI3K/AKT/mTOR signaling pathway. Based on these findings, it is concluded that NT-3 can bidirectionally regulate autophagy in oligodendrocytes through the switching of P75NTR/TrkC receptors, thereby maintaining cell survival and facilitating the recovery of neurological functions in rats after spinal cord injury.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: neurotrophin-3, autophagy, oligodendrocyte, receptor switching, apoptosis, spinal cord injury