Repetitive transcranial magnetic stimulation (rTMS) influences spatial cognition and modulates hippocampal structural synaptic plasticity in aging mice

• Cognitive deficit of aging is related to hippocampal synaptic structural plasticity.
• Low- or high-intensity rTMS affects spatial cognition in aging mice differently.
• rTMS modulates the ultrastructures of hippocampal neurons and synapses in aging mice.
• rTMS changes synaptic protein markers and BDNF–TrkB levels in aging mice.
• rTMS regulated cognition is related to structural synaptic plasticity and BDNF signal.

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 (≤ 1 Hz) 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, 1 Hz, 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, 1 Hz, 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.