title: Repetitive transcranial magnetic stimulation (rTMS) influences spatial cognition and modulates hippocampal structural synaptic plasticity in aging mice.
abstract: Normal aging is characteristic with the gradual decline in cognitive function associated with the progressive reduction of structural and functional plasticity in the hippocampus. Repetitive transcranial magnetic stimulation (rTMS) has developed into a novel neurological and psychiatric tool that can be used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency rTMS (≤1Hz) affects synaptic plasticity in rats with vascular dementia (VaD), and it ameliorates the spatial cognitive ability in mice with Aβ1-42-mediated memory deficits, but there are little concerns about the effects of rTMS on normal aging related cognition and synaptic plasticity changes. Thus, the current study investigated the effects of rTMS on spatial memory behavior, neuron and synapse morphology in the hippocampus, and synaptic protein markers and brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) in normal aging mice, to illustrate the mechanisms of rTMS in regulating cognitive capacity. Relative to adult animals, aging caused hippocampal-dependent cognitive impairment, simultaneously inhibited the activation of the BDNF-TrkB signaling pathway, reduced the transcription and expression of synaptic protein markers: synaptophysin (SYN), growth associated protein 43 (GAP43) and post-synaptic density protein 95 (PSD95), as well as decreased synapse density and PSD (post-synaptic density) thickness. Interestingly, rTMS with low intensity (110% average resting motor threshold intensity, 1Hz, LIMS) triggered the activation of BDNF and TrkB, upregulated the level of synaptic protein markers, and increased synapse density and thickened PSD, and further reversed the spatial cognition dysfunction in aging mice. Conversely, high-intensity magnetic stimulation (150% average resting motor threshold intensity, 1Hz, HIMS) appeared to be detrimental, inducing thinning of PSDs, disordered synaptic structure, and a large number of lipofuscin accumulations, as well as reducing the number of synapses and downregulating BDNF-TrkB and synaptic proteins. Ultimately, HIMS further impaired the capacity for learning and memory. In conclusion, we infer that aging-induced cognitive deficits are closely associated with hippocampal structural synaptic plasticity, and low-frequency magnetic stimulation plays an important role in regulating cognitive behavior via changing structural synaptic plasticity, and BDNF signaling might participate in this event.
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, PR China; Hebei Key Laboratory for Brain Aging and Cognitive Neuroscience, Shijiazhuang 050031, Hebei, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, PR China.
authors.forename: Zhanchi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, PR China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Geng
authors.affiliation: Hebei Key Laboratory for Brain Aging and Cognitive Neuroscience, Shijiazhuang 050031, Hebei, PR China; First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei, PR China.
authors.forename: Yanyong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Hebei Key Laboratory for Brain Aging and Cognitive Neuroscience, Shijiazhuang 050031, Hebei, PR China; First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei, PR China.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, PR China; Hebei Key Laboratory for Brain Aging and Cognitive Neuroscience, Shijiazhuang 050031, Hebei, PR China. Electronic address: cuihuixianky@yahoo.com.
authors.forename: Huixian
authors.initials: H
authors.lastname: Cui
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003071:Cognition; D000076122:Disks Large Homolog 4 Protein; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology* / Q000648:ultrastructure; D007858:Learning; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008568:Memory; D051379:Mice; D009473:Neuronal Plasticity; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D013028:Space Perception; D009435:Synaptic Transmission; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D050781:Transcranial Magnetic Stimulation
chemical_list: D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D019922:GAP-43 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D016708:Synaptophysin; C569015:Syp protein, mouse; D020813:Receptor, trkB; D051528:Guanylate Kinases
keywords: Aging; Cognition; Hippocampus; Repetitive transcranial magnetic stimulation (rTMS); Synaptic plasticity