Abstract
Synaptic impairment results in cognitive dysfunction of Alzheimer’s disease (AD). As a plant extract, it is found that DL-3-n-butylphthalide (L-NBP) rescues abnormal cognitive behaviors in AD animals. However, the regulatory effects of L-NBP on synaptic plasticity remains unclear. APP/PS1 mice at 12 months old received oral L-NBP treatment for 12 weeks. A water maze test assessed cognitive performances. In vitro patch-clamp recordings and in vivo field potential recordings were performed to evaluate synaptic plasticity. The protein expression of AMPA receptor subunits (GluR1 and GluR2) and NMDA receptor subunits (NR1, NR2A, and NR2B) was examined by Western blot. In addition, glutaminase activity and glutamate level in the hippocampus were measured by colorimetry to evaluate presynaptic glutamate release. L-NBP treatment could significantly improve learning and memory ability, upregulate NR2A and NR2B protein expressions, increase glutaminase activity and glutamate level in the hippocampus, and attenuate synaptic impairment transmission in the AD mice. L-NPB plays a beneficial role in AD mice by regulating NMDA receptor subunits’ expression and regulating presynaptic glutamate release.
Highlights
Learning and memory impairment is one of the typical symptoms of Alzheimer’s disease (AD)
The durations in the target quadrant among four groups were significantly different (P < 0.01). It indicated that WT mice spent considerably more time in the target quadrant than Tg mice (P < 0.01), while Tg mice treatment with L-NBP could dramatically increase the time in the target quadrant (P < 0.05) (Fig. 1c)
The present study reveals that L-NBP improved cognitive performances in AD mice, which is consistent with previous findings that L-NBP could enhance learning and memory through Morris water maze test in various experimental AD models, including Aβ intracerebroventricularly infused rats, double transgenic APP/PS1 mice, and triple transgenic 3xTg-AD mice [10, 11, 15]
Summary
Learning and memory impairment is one of the typical symptoms of Alzheimer’s disease (AD). Synaptic function underlies the mechanism of memory formation and storage [1], and synaptic impairment was suggested to be the basis of memory dysfunction in AD [2]. Synaptic changes were identified in AD mice, such as APP/PS1 mice and Tg2576 These changes included synaptic loss, decreased spine density, and long-term potentiation (LTP) impairments [4]. Chemicals that were shown to attenuate learning and memory deficits in experimental AD animals could prevent the impairment of synaptic function [5,6,7]. L-NBP could rescue hippocampal synaptic loss in aged APP/PS1 mice [14]. It is not clear whether L-NBP modulates synaptic plasticity. We sought to determine the effects of L-NBP on synaptic plasticity of APP/PS1 mice and investigate the possible underlying mechanisms
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