title: Simvastatin Enhances Spatial Memory and Long-Term Potentiation in Hippocampal CA1 via Upregulation of α7 Nicotinic Acetylcholine Receptor.
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.
authors.affiliation: Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China. chenl@njmu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory of Reproductive Medicine, Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China. lingchen@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005204:Farnesol / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D065852:Spatial Memory / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D005204:Farnesol; D005971:Glutamates; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019821:Simvastatin; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Farnesyl pyrophosphate (FPP); Hippocampus; Long-term potentiation (LTP); Simvastatin; Spatial cognition; α7 Nicotinic acetylcholine receptor (α7nAChR)