title: Improvement of spatial learning by facilitating large-conductance calcium-activated potassium channel with transcranial magnetic stimulation in Alzheimer's disease model mice.
abstract: Transcranial magnetic stimulation (TMS) is fragmentarily reported to be beneficial to Alzheimer's patients. Its underlying mechanism was investigated. TMS was applied at 1, 10 or 15 Hz daily for 4 weeks to young Alzheimer's disease model mice (3xTg), in which intracellular soluble amyloid-β is notably accumulated. Hippocampal long-term potentiation (LTP) was tested after behavior. TMS ameliorated spatial learning deficits and enhanced LTP in the same frequency-dependent manner. Activity of the large conductance calcium-activated potassium (Big-K; BK) channels was suppressed in 3xTg mice and recovered by TMS frequency-dependently. These suppression and recovery were accompanied by increase and decrease in cortical excitability, respectively. TMS frequency-dependently enhanced the expression of the activity-dependently expressed scaffold protein Homer1a, which turned out to enhance BK channel activity. Isopimaric acid, an activator of the BK channel, magnified LTP. Amyloid-β lowering was detected after TMS in 3xTg mice. In 3xTg mice with Homer1a knocked out, amyloid-β lowering was not detected, though the TMS effects on BK channel and LTP remained. We concluded that TMS facilitates BK channels both Homer1a-dependently and -independently, thereby enhancing hippocampal LTP and decreasing cortical excitability. Reduced excitability contributed to amyloid-β lowering. A cascade of these correlated processes, triggered by TMS, was likely to improve learning in 3xTg mice.
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Furong
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Medical College, Qinghai University, Xinin 810016, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; China-Japan Friendship Hospital, Beijing 100029, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xianwen
authors.initials: X
authors.lastname: Luo
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ishigaki
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Tokio
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamamoto
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan. Electronic address: kato@kanazawa-med.ac.jp.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology* / Q000628:therapy*; D000818:Animals; D002264:Carboxylic Acids / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D000072233:Homer Scaffolding Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D049990:Membrane Transport Modulators / Q000494:pharmacology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010616:Phenanthrenes / Q000494:pharmacology; D046509:Tissue Culture Techniques; D050781:Transcranial Magnetic Stimulation
chemical_list: D002264:Carboxylic Acids; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D049990:Membrane Transport Modulators; D010616:Phenanthrenes; C115138:isopimaric acid
keywords: Alzheimer's disease; Homer 1a; Large-conductance calcium-activated potassium channel; Synaptic plasticity; Transcranial magnetic stimulation