Aerobic Exercise Alleviates Defective Metaplasticity In A Mouse Model Of Alzheimer's Disease

Abstract

PURPOSE: Metaplasticity plays an important role in neural circuits to operate within normal functional ranges, which was found to be defective in Alzheimer’s disease (AD) models. Our previous studies have demonstrated that aerobic exercise could improve synaptic plasticity by increasing absolute magnitudes of long-term potentiation (LTP) and decreasing long-term depression (LTD) in APP/PS1/Tau transgenic (Tg) mice. While LTP and LTD are not static, their induction threshold is adjusted by metaplasticity. Hence, this study aimed to investigate whether aerobic exercise improving neuroplasticity is associated with metaplasticity in Tg mice. METHODS: Tg mice were randomly assigned to two groups (sedentary, AS; exercise, AE). Tg mice at 2-month-old (an early stage) started treadmill exercise for 4 months until 6-month-old (a moderate pathological stage). The non-Tg mouse strain was used as a control (CS, CE). Patch-clamp was used to record the basal synaptic functions (I-O Curve; PPR) and the frequency-dependent synaptic plasticity in hippocampal area CA1. Five different stimulation frequency protocols (1 Hz, 5 Hz, 10 Hz, 50 Hz, TBS) were chosen to reflect the metaplasticity. RESULTS: In Tg mice, there was a significant decrease in I-O curve (CS, 0.27 ± 0.04; AS, 0.14 ± 0.02; P < 0.01). Exercise increased I-O curve (CS, 0.27 ± 0.04; CE, 0.68 ± 0.12; AS, 0.14 ± 0.02; AE, 0.42 ± 0.05; CS vs. CE, P < 0.01; AS vs. AE, P < 0.01). There was a significant increase in PPR in Tg mice at the interval time of 20 ms (CS, 1.74 ± 0.08; AS, 2.08 ± 0.11; P < 0.01). Exercise reversed the changes of PPR (AS, 2.08 ± 0.11; AE, 1.67 ± 0.08; P < 0.05). In Tg mice, exercise increased LTP at the frequency of TBS [fEPSP slope (%): AS, 176.53 ± 13.55; AE, 209.86 ± 10.27; P < 0.05]. AS group induced reliable LTP at 50 Hz (158.36 ± 6.10) and TBS (176.53 ± 13.55). While the AE group induced reliable LTP at 5 Hz (126.89 ± 3.78), 10 Hz (122.17 ± 6.66), 50 Hz (184.12 ± 15.41), TBS (209.86 ± 10.27). Exercise decreased the modification threshold (AS vs. AE, P < 0.05), which suggested the induction threshold was shifted to the left in favor of LTP. CONCLUSIONS: These results suggest that aerobic exercise could enhance LTP by normalizing metaplasticity by decreasing the modification threshold in Tg mice. Supported by the National Natural Science Foundation of China (NSFC) (No. 31571229).