Postoperative cognitive dysfunction (POCD) is a disturbing neurological complication in patients undergoing anesthesia and surgical procedures. Brain-derived neurotrophic factor (BDNF) and its precursor proBDNF binding to their corresponding receptors tyrosine kinase (TrkB) and p75 neurotrophin receptor (p75NTR) exert quite an opposite biological function in neuron survival and synaptic function. This study aimed to demonstrate the critical role of the BDNF/proBDNF ratio in modulating synaptic plasticity, which further leads to anesthesia-/surgery-induced POCD. It also showed that the exogenous BDNF or p75NTR inhibitor could ameliorate cognitive dysfunction. In detail, 16-month-old C57BL/6 mice were subjected to a stabilized tibial fracture surgery with isoflurane anesthesia to establish the POCD animal model. The mice were then microinjected with either p75NTR inhibitor or exogenous BDNF into the dorsal hippocampus. Behavioral experiments were performed by open field and fear conditioning tests (FCTs). Western blotting was also used to measure the expression levels of BDNF, proBDNF, TrkB, p-TrkB, p75NTR, and synapse proteins. Golgi staining and electrophysiology were applied to evaluate the neuronal synaptic plasticity. Here, we demonstrated that anesthesia/surgery induced a reduction of BDNF/proBDNF, which negatively regulates the synaptic function in hippocampus, subsequently leading to cognitive impairment in aged mice. P75NTR inhibitor and exogenous BDNF could attenuate cognitive deficits by rescuing the dendritic spine loss and long-term potentiation (LTP) via altering the BDNF/proBDNF ratio. This study unveiled that the BDNF/proBDNF ratio in the hippocampus played a key role in anesthesia-/surgery-induced POCD. Thereby, tuning the ratio of BDNF/proBDNF is supposed to be a promising therapeutic target for POCD.

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