Repetitive transcranial magnetic stimulation increases synaptic plasticity of cortical axons in the APP‐PS1 mouse model of amyloidosis

Abstract

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS) is non‐invasive brain stimulation with therapeutic potential for use in diseases causing dementia. We previously demonstrated that low intensity (LI) rTMS induced functional improvements in the accuracy and rate of learning in adult mouse skilled reaching paradigms (Tang, Bennett et al, Scientific Reports, 2018) and induced dendritic spine changes in cortical motor neurons after a single application of LI‐rTMS (Tang, Bennett et al, Brain Stimulation, 2021). Here, we investigate the effect of LI‐rTMS on axonal boutons of excitatory axons in the presence of amyloid pathology in the APP‐PS1 mouse.MethodAPP/PS1 mice were crossed with Thy1‐GFPM mice to visualise excitatory axon circuitry in the presence of amyloid plaque pathology. Multiphoton imaging through a cranial window was used to identify cortical axons in the upper layers of the sensorimotor cortex in adult animals (10‐12 months old) and monitor the stability and turnover (gains and losses as a fraction of total number of synapses) of axonal boutons in the presence (APP‐GFPM) or absence (WT‐GFPM) of amyloid pathology. Axons were imaged at 48‐hour intervals for 8 days either side of a single session of LI‐rTMS.ResultThe density of axonal boutons along the axon shaft was stable and comparable in APP‐GFPM and WT‐GFP mice, before and after LI‐rTMS. The turnover of synapses was significantly (p < 0.05) reduced in APP‐GFPM cortical axons compared to WT‐GFPM prior to stimulation. A single session of LI‐rTMS induced a significant (p < 0.01)and sustained increase in synaptic turnover in both genotypes. Interestingly the initial lower turnover of boutons in the APP‐GFPM cortex was increased to the levels observed in WT‐GFPM axons at baseline.ConclusionIn the presence of amyloid pathology, synaptic density in excitatory cortical axons is unchanged, however the dynamic fraction of synapses is reduced in compared to aged‐matched controls. LI‐rTMS boosts synaptic plasticity in mature cortical axons in both the presence and absence of plaque pathology. Together with our findings of improved functional performance following stimulation, these results suggest not only possible mechanisms of action but also a potential clinical benefit in the management of Alzheimer’s disease.