Live Imaging Reveals Axon Adaptability in Neuroplasticity

Summary: For the first time, researchers observed nerve plasticity within the axon in real-time. This adaptability focuses on the axon initial segment (AIS), a vital nerve cell component initiating electrical signals.

The study highlights the rapid change in sodium channels in this segment, crucial for balancing neural activity. This groundbreaking research combines unique tools and expertise, shedding light on the intricate processes behind learning and memory.

Key Facts:

  1. The axon initial segment (AIS) acts as a nerve cell’s control center, determining when electrical signals are initiated.
  2. AIS plasticity allows for rapid changes in sodium channels, ensuring neural activity balance and optimal memory formation.
  3. Through innovative techniques, the research team achieved live imaging of these changes, offering unprecedented insight into axon adaptability.

Source: KNAW

Researchers from the Netherlands Institute for Neuroscience have, for the first time, witnessed nerve plasticity in the axon in motion.

Our nerve cells communicate through rapid transmission of electrical signals known as action potentials. All action potentials in the brain start in one unique small area of the cell: the axon initial segment (AIS).

This is the very first part of the axon, the long, thin extension of a nerve cell that transmits signals or impulses from one nerve cell to another. It acts as a control center where it is decided when an action potential is initiated before traveling further along the axon.

This shows a neuron.
But how this works and how fast this plasticity occurs have always been fundamental questions for neuroscientists. Credit: Neuroscience News

Previously, researchers made the surprising observation that plasticity also occurs at the AIS. Plasticity refers to the brain’s ability to create new connections and structures in order to scale the amount of electrical activity, which is crucial for learning and memory. AIS plasticity occurs during changes in brain network activity.

The segment’s length can become shorter with excessive activity or longer with low activity. But how does this structure change, and how quickly does it happen? Amélie Fréal and Nora Jamann in the lab of Maarten Kole have, for the first time, observed in real-time how this adaptability functions within the axon and identified the molecular mechanisms behind this process.

Essential Gates

Key players in this process are ion gates located at the segment, also known as sodium channels. The team developed new tools to study these sodium channels and their supporting proteins. They discovered that the number of sodium channels in the cell’s segment can change rapidly, within an hour. This rapid change is mediated by a process called endocytosis, in which the sodium channels are taken up into vesicles within the cell.

Nora Jamann explains, “You can think of this adaptability as a kind of amplifier that allows you to fine-tune the input. The longer the AIS, the less current you need. You can enhance the cell’s output. If this isn’t properly adjusted, learning can be compromised.”

“When you learn, the activity in the neural network constantly fluctuates. Neurons need to operate with extreme variations in levels of activity—both too low and too high activity can be harmful for memory formation.’

Her previous experiments in mice illustrate this adaptability: a mouse with clipped whiskers receives reduced sensory input. As a result, the number of sodium channels in the AIS increases to maintain balance.

The opposite also occurs: if there is too much input, such as when the mouse is placed in a new environment with high activity, the AIS becomes slightly shorter and has fewer sodium channels. But how this works and how fast this plasticity occurs have always been fundamental questions for neuroscientists.

Live imaging

Amélie Fréal says, “To address this question, we faced a significant challenge: how can we capture plasticity live? If you wonder how the AIS adapts, you want to actually see it moving.

This was not previously possible in the field. In this research, we used two new tools: first, a special mouse model with the AIS labeled with a fluorescent protein, allowing us to observe the mechanism and record the temporal changes in brain slices. Second, we used molecular tools that made sodium channels visible in cell cultures. This made it possible to track the sodium channels live for the first time.”

Jamann continues, “The plasticity we observe in the AIS closely resembles what we know about synaptic plasticity. This is the most well-known form of plasticity and relates to the ability of the connection (the synapse) between two nerve cells to change in strength. Synaptic plasticity is directly linked to learning and memory. But the same mechanism also occurs in the AIS.”

Amélie Fréal adds, “If you want to be a bit provocative, you can even say that a lot of change occurs in the synapse, but only the relevant information is forwarded to the next nerve cell. This decision is made in the AIS, so changes in this region are genuinely important for the cell’s function.”

Fréal concludes, “This study brings together different areas of expertise, which I strongly support in research. Maarten Kole’s lab has all the equipment to record and see the activity, and I came with novel tools to image the nanoscale structures.

“Together, we have been able to establish that when activity changes, structure changes as well. This observation will help us see plasticity in a broader perspective. When looking at plasticity in general, we now need to consider these changes in the AIS.

“Through this collaboration, we have been able to combine our strengths to advance knowledge. That’s what I’m most proud of.”

About this neuroplasticity research news

Author: Eline Feenstra
Source: KNAW
Contact: Eline Feenstra – KNAW
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Sodium channel endocytosis drives axon initial segment plasticity” by Maarten Kole et al. Science Advances


Sodium channel endocytosis drives axon initial segment plasticity

Activity-dependent plasticity of the axon initial segment (AIS) endows neurons with the ability to adapt action potential output to changes in network activity. Action potential initiation at the AIS highly depends on the clustering of voltage-gated sodium channels, but the molecular mechanisms regulating their plasticity remain largely unknown.

Here, we developed genetic tools to label endogenous sodium channels and their scaffolding protein, to reveal their nanoscale organization and longitudinally image AIS plasticity in hippocampal neurons in slices and primary cultures.

We find that N-methyl-d-aspartate receptor activation causes both long-term synaptic depression and rapid internalization of AIS sodium channels within minutes. The clathrin-mediated endocytosis of sodium channels at the distal AIS increases the threshold for action potential generation.

These data reveal a fundamental mechanism for rapid activity-dependent AIS reorganization and suggests that plasticity of intrinsic excitability shares conserved features with synaptic plasticity.

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