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Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor

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Abstract

Simvastatin (SV) has been reported to improve cognitive deficits in Alzheimer’s disease. Here, we show that chronic administration of SV (20 mg/kg) for 30 days in adult mice (SV mice) enhanced spatial cognitive performance as assessed by Morris water maze and Y-maze. To explore mechanisms underlying SV-enhanced spatial cognition, we further examined synaptic properties and long-term potentiation (LTP) in hippocampal CA1, hippocampal α7nAChR expression, and Akt and ERK2 phosphorylation. In comparison with controls, the SV administration caused increase in presynaptic glutamate release and amplitude of NMDAr-dependent LTP (LTP-augmentation), and decrease in threshold of NMDAr-independent LTP induction (LTP-facilitation). The supplement of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the spatial cognitive potentiation, increased glutamate release, and LTP-augmentation/facilitation in SV mice. Expression of α7nAChR, but not α4β2nAChR, was increased in hippocampal pyramidal cells of SV mice with the reduction of transcription factor AP-2α, which were abolished by FOH. Levels of Akt and ERK2 phosphorylation in SV mice were elevated, which were suppressed by FOH or α7nAChR antagonist methyl-lycaconitine (MLA). In hippocampal slices obtained from SV mice, acute perfusion of MLA blocked the increased glutamate release, whereas FOH, PI3K inhibitor LY294002, or MEK inhibitor U0126 could not. In the slices of SV mice, the perfusion of MLA or U0126, but not FOH, abolished the LTP-augmentation and LTP-facilitation. By contrast, LY294002 prevented the LTP-facilitation but failed to affect the LTP-augmentation. The findings indicate that the administration of SV through reducing FPP increases α7nAChR expression and α7nAChR-related Akt and ERK2 phosphorylation, leading to LTP enhancement and spatial cognitive potentiation.

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Acknowledgments

This work was supported by grants for National 973 Basic Research Program of China (2014CB943303) and National Natural Science Foundation of China (81071027; 31171440; 81361120247; 31271206) to Chen L.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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  1. Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China

    Tingting Chen, Conghui Wang, Sha Sha, Libin Zhou, Lei Chen & Ling Chen

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  2. Conghui Wang
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Correspondence to Lei Chen or Ling Chen.

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(1) Chronic administration of simvastatin (SV) enhances spatial memory in mice.

(2) SV enhances hippocampal Schaffer collateral-CA1 synaptic glutamate release and LTP induction in α7nAChR-dependent manner.

(3) SV through reducing farnesyl pyrophosphate increases α7nAChR expression and activity to cascade PI3K-Akt and ERK signaling pathways.

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Chen, T., Wang, C., Sha, S. et al. Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor. Mol Neurobiol 53, 4060–4072 (2016). https://doi.org/10.1007/s12035-015-9344-6

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