title: Atorvastatin enhances kainate-induced gamma oscillations in rat hippocampal slices.
abstract: Atorvastatin has been shown to affect cognitive functions in rodents and humans. However, the underlying mechanism is not fully understood. Because hippocampal gamma oscillations (γ, 20-80 Hz) are associated with cognitive functions, we studied the effect of atorvastatin on persistent kainate-induced γ oscillation in the CA3 area of rat hippocampal slices. The involvement of NMDA receptors and multiple kinases was tested before and after administration of atorvastatin. Whole-cell current-clamp and voltage-clamp recordings were made from CA3 pyramidal neurons and interneurons before and after atorvastatin application. Atorvastatin increased γ power by ~ 50% in a concentration-dependent manner, without affecting dominant frequency. Whereas atorvastatin did not affect intrinsic properties of both pyramidal neurons and interneurons, it increased the firing frequency of interneurons but not that of pyramidal neurons. Furthermore, whereas atorvastatin did not affect synaptic current amplitude, it increased the frequency of spontaneous inhibitory post-synaptic currents, but did not affect the frequency of spontaneous excitatory post-synaptic currents. The atorvastatin-induced enhancement of γ oscillations was prevented by pretreatment with the PKA inhibitor H89, the ERK inhibitor U0126, or the PI3K inhibitor wortmanin, but not by the NMDA receptor antagonist D-AP5. Taken together, these results demonstrate that atorvastatin enhanced the kainate-induced γ oscillation by increasing interneuron excitability, with an involvement of multiple intracellular kinase pathways. Our study suggests that the classical cholesterol-lowering agent atorvastatin may improve cognitive functions compromised in disease, via the enhancement of hippocampal γ oscillations.
authors.affiliation: Key Lab of Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China.
authors.forename: Chengzhang
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Lab of Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Key Lab of Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Lab of Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Lab of Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China.
authors.forename: Fang Li
authors.initials: FL
authors.lastname: Guo
authors.affiliation: Key Lab of Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China.
authors.forename: Xiao Fang
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Department of Psychology, Xinxiang Medical University, Xinxiang, China.|School of Health and Education, Birmingham City University, Birmingham, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Vreugdenhil
authors.affiliation: Key Lab of Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, 453003, P.R. China.
authors.forename: Cheng Biao
authors.initials: CB
authors.lastname: Lu
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000069059:Atorvastatin / Q000009:adverse effects / Q000494:pharmacology*; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D065818:Gamma Rhythm; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D000924:Anticholesteremic Agents; D018690:Excitatory Amino Acid Agonists; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D000069059:Atorvastatin; D007608:Kainic Acid
keywords: extracellular signal-regulated kinase; hippocampus; interneurons; phosphatidylinositol 3-kinase; protein kinase A; pyramidal neurons