The Effects of Treadmill Exercise on the Recovery of Synaptic Plasticity in Septic Mice: A Focus on Brain-Derived Neurotrophic Factor/Tropomyosin-Related Kinase B Signaling.

Abstract

BACKGROUND Sepsis-associated encephalopathy causes irreversible cognitive dysfunction, yet no effective pharmacological treatments are available. The hippocampus is particularly vulnerable to sepsis-induced damage, and impairments in hippocampal synaptic plasticity, particularly late-phase long-term potentiation (L-LTP), are implicated in cognitive dysfunction. Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), play crucial roles in maintaining L-LTP. While exercise enhances cognitive function, its effects on hippocampal synaptic plasticity under conditions mimicking early rehabilitation after sepsis remain unclear. This study evaluated the impact of treadmill exercise on hippocampal L-LTP in a murine sepsis model, using a protocol resembling early clinical rehabilitation. METHODS A total of 267 C57BL/6J mice (8-12 weeks old) underwent cecal ligation and puncture (CLP) or sham surgery, with or without treadmill exercise (30 min/d for 7 days postsurgery). Mice were divided into 4 groups: (1) sham + sedentary, (2) sham + exercise, (3) CLP + sedentary, and (4) CLP + exercise. The primary outcome was hippocampal L-LTP, assessed via electrophysiology. Secondary outcomes included hippocampal BDNF levels, locomotor activity, and survival curves. Additionally, the role of BDNF/TrkB signaling was examined using ANA-12, an antagonist of the BDNF receptor TrkB. Data are presented as mean ± standard deviation. RESULTS L-LTP at the Schaffer collateral-CA1 synapse was significantly impaired in CLP mice 1 week after surgery (CLP + sedentary: 144% ± 15% vs sham + sedentary: 185% ± 34%; P = .008). Exercise restored L-LTP in CLP mice (CLP + exercise: 189% ± 36% vs CLP + sedentary: 144% ± 15%, P = .003), but this effect was abolished by ANA-12 (CLP + exercise + ANA-12: 155% ± 22% vs CLP + exercise + vehicle: 194% ± 37%, P < .001). Exercise also restored hippocampal BDNF levels reduced by CLP (CLP + exercise: 4190 ± 671 pg/mg protein versus CLP + sedentary: 3220 ± 647 pg/mg protein, P = .007). Locomotor activity was impaired in CLP mice but not significantly improved by exercise (P = .38). Furthermore, the survival curves differed significantly between CLP mice with and without treadmill exercise, as determined by post hoc analysis after a log-rank test (P = .003). CONCLUSIONS Treadmill exercise therapy restored hippocampal L-LTP impaired by sepsis, at least partially mediated by activation of the BDNF/TrkB signaling pathway. Additionally, exercise altered the survival curve, though it had limited effects on locomotor activity. These findings suggest that exercise therapy may mitigate sepsis-induced synaptic dysfunction.