Summary: New research shows that repetitive low-intensity transcranial magnetic stimulation (rTMS) can restore important synaptic structures in a mouse model of Alzheimer’s disease. The study revealed that axonal boutons the connection points between neurons in mice with Alzheimer’s had decreased neuronal turnover, indicating impaired brain plasticity.
After a single rTMS session, there was a significant increase in the turnover of one type of button, reaching levels observed in healthy mice. These changes suggest that rTMS can partially reverse synaptic deficits and thus potentially improve brain connectivity.
Important facts:
- Synaptic Business Growth: rTMS boosted terminal button turnover in Alzheimer’s mice by up to 213%, promoting synaptic growth.
- Selected answer: Only the terminal buttons, not the step buttons, respond to rTMS.
- Treatment potential: rTMS restored impaired synaptic plasticity to near healthy levels.
Source: SPIE
Alzheimer’s disease (AD) is a devastating neurological condition impacting many older adults globally. Synapses, the communication points between neurons, adapt through experience by adding, removing, or modifying connections, allowing the brain to encode new memories or forget old ones.
In Alzheimer’s disease, synaptic plasticity (the brain’s ability to regulate the strength of synaptic connections between neurons) is significantly impaired. This deteriorates over time, leading to cognitive and memory impairment and reduced quality of life. There is currently no effective cure for Alzheimer’s, and treatment options for managing symptoms are limited.
Research shows that repetitive transcranial magnetic stimulation (rTMS), a non-invasive technique using targeted electromagnetic pulses, holds promise for treating dementia and related conditions. Earlier studies have also demonstrated that rTMS can enhance synaptic plasticity in a healthy nervous system.
In addition, it is already used to treat certain neurodegenerative and neuropsychiatric disorders. However, individual responses to rTMS in the treatment of Alzheimer’s disease vary, and the underlying mechanisms are not yet fully understood.
Recently, researchers from the University of Queensland and the University of Tasmania’s Viking Dementia Research and Education Centre studied how rTMS affects synapses in the cerebral cortex of mice with Alzheimer’s disease.
Their report was published in Neurophotonics. “Because synaptic dysfunction is a key mechanism in Alzheimer’s disease, in this study we assessed changes in synaptic axonal synaptic plasticity in a mouse model of Alzheimer’s disease in response to rTMS and compared them with healthy mice,” explains Dr. Barbora Flopova, corresponding author and postdoctoral fellow at the University of Prague.
Axon ganglia are specialized terminals of axons, the long, thin part of neurons that connects neurons and transmits neuronal signals. Synapses form at these sites, enabling communication between neurons.
Therefore, any change in the number or function of these boutons can have a profound impact on brain connectivity. In this study, the researchers observed structural changes in two types of excitatory boutons: terminal boutons (TBs) (short projections with axon shafts that typically connect neurons in a local area) and en passant boutons (EPBs) (small, spherical structures with axons that typically connect distant areas). They used two-photon imaging to visualize individual axons and synapses in the brain of a living animal.
The study was conducted using mice of the APP/PS1 xThy-1GFP-M strain, a cross between the APP/PS1 strain (genetically modified to exhibit AD-like symptoms in humans) and the Thy1-GFP-M strain, which produces a fluorescent protein in certain neurons. This combination causes axons to glow during imaging, allowing precise tracking of changes in synaptic terminals over time.
The team monitored the dynamics of the axonal glands of these mice for eight days at 48-hour intervals, before and after a single rTMS session. They then compared these results with those of healthy wild-type (WT) mice.
They found that both boutons and EPBs showed increased density in the Alzheimer’s mouse model compared to healthy wild-type mice. However, the turnover of both boutons was significantly lower in the AD mouse model before rTMS, likely due to the accumulation of amyloid plaques, a key marker of dementia and a potential trigger for diseases such as AD.
After a single session of low-intensity rTMS, there was a significant increase in tubercle turnover in both Alzheimer’s and healthy mice. However, no change was observed in EPB turnover following the treatment. This suggests that rTMS selectively affects certain synaptic components. The findings highlight the potential of rTMS to promote synaptic plasticity. Further research is needed to understand the long-term effects.
Notably, the largest changes occurred two days after stimulation, with an 88% increase in tubercle turnover in the WT strain and a 213% increase in the APP-GFP strain. However, this increase returned to pre-stimulation levels by eight days. Moreover, this increase in cell turnover in the AD mouse model was comparable to the values observed in WT mice before stimulation. This suggests that low-intensity rTMS can restore T cell (TB) synaptic plasticity to levels observed in healthy mice.
The selective response of terminal boutons (TBs) — but not en passant boutons (EPBs) — to rTMS indicates that its effects may vary depending on the type of neuron involved. This points to a more targeted action of brain stimulation on specific neural connections. Filopova noted, “This is the first study showing that presynaptic connections react to rTMS in both healthy brains and those affected by dementia,” highlighting the promising potential of rTMS as a precise treatment for neurological disorders.
“Given the established link between synaptic dysfunction and cognitive decline in dementia and the use of rTMS to treat other neurodegenerative diseases, our results highlight its potential as an effective addition to currently used AD treatment strategies.”
This study marks an important step forward in our understanding of Alzheimer’s disease. By uncovering how rTMS influences specific synaptic connections, researchers have gained valuable insights into the underlying mechanisms of the condition.
While more research is still needed to confirm and expand on these results, the findings offer hope for developing targeted rTMS treatments. Such therapies could potentially improve cognitive function and overall quality of life for people living with Alzheimer’s.
Abstract
Repetitive transcranial magnetic stimulation enhances synaptic plasticity of cortical axons in a mouse model of APP/PS1 amyloidosis.
Significance
There is growing evidence of the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) for dementias such as Alzheimer’s disease. However, responses to rTMS vary from person to person, and the underlying neural mechanisms are not yet fully understood.
Aim
Since synaptic dysfunction is a key factor behind cognitive decline in dementia, we explored how rTMS affects cortical synapses. For this, we used the APP/PS1 amyloidosis Alzheimer’s mouse model combined with fluorescent reporters controlled by the Thy-1 promoter.
This approach allowed us to closely observe changes at the synaptic level, helping to better understand how brain stimulation might counteract the synaptic problems seen in Alzheimer’s disease.
Approach
Using in vivo two-photon imaging, we characterized the plasticity of excitatory terminals (TBs) and en passant axon boutons (EPBs) at 48-hour intervals before and after a single rTMS session.
Results
We observed that both types of stimulated axons maintained their total number of synaptic outputs in both the wild-type (WT) and APP/PS1 groups, both before and after stimulation. However, before stimulation, the active fraction of synapses was significantly lower in the APP/PS1 axons compared to the WT.
Following stimulation, the active fraction of terminal boutons (TB) increased in both WT and APP/PS1 groups, while no change was seen in the active fraction of en passant boutons (EPB). This suggests a selective effect of rTMS on specific synapse types across both healthy and Alzheimer’s models.
Results
This points to potential cell type-specific mechanisms behind how rTMS works. Along with earlier findings showing improved brain function, this supports the possibility of using rTMS as a clinical treatment for Alzheimer’s disease.
