How do the Brain and Nervous System Send Signals to Protect us from Harm?

Since I was a child, I have wondered which of the body’s organs are the most complex and important. As I grew older, I realized it was the brain—with its amazing control over the body through the nervous system. The brain not only controls every intentional action, like moving our hands or walking, but it also protects us from harm. For example, when a person touches something harmful, like a sharp knife or a hot object, the nervous system quickly sends signals to help the person avoid getting hurt. It is fascinating how this system keeps us safe.

There are two main parts of the nervous system: the main nervous system, which is called the central nervous system and includes the brain and spinal cord; and the branching network that extends through the whole body, called the peripheral nervous system [1]. The nervous system is made up of neurons, which are cells that have a cell body, one long wire-like branch (covered in a fatty coating that speeds up signals), and many small antenna-like branches that receive signals from other neurons [2]. Signals race along these wires to the brain and spinal cord so the body can pull away from danger. Later in the article, we will explain how, when such signals become too strong or last too long, they can harm the brain cells themselves.

Neurotransmission is the term for the movement of information between neurons. Neurotransmission happens in the tiny space between neurons, called the synapse, and involves an electrical signal that is carried by charged particles called ions—primarily sodium, potassium, and calcium ions. In the synapse, the neurons contain “gates” called AMPA receptors, which allow key messages to pass into cells and give the brain the ability to adapt (Figure 1) [3].

AMPA receptors on brain cells help the cells pass messages quickly. These receptors are crucial for learning and memory. When the brain sends a message, it releases a substance called glutamate, which binds to AMPA receptors and opens them, allowing ions to enter the cell and pass the message along. If AMPA receptors do not work properly, brain function can be affected. Because early evidence links AMPA-receptor breakdown to the first stages of memory loss in Alzheimer’s disease, understanding how certain substances could steady these receptors could point to new treatments.

For example, changes in the “building blocks” that make up the AMPA receptors can let too much calcium into the cell and cause damage from overactivity, which harms the brain. Changes in the genes that regulate AMPA receptors can also disrupt their movement to and from the synapse—a process where the brain sends more receptors to the cell surface when it needs stronger signals and pulls the receptors back inside the cell when it wants to reduce the signal. If this balance is disturbed, brain cells may not send messages properly, which affects brain signaling [4]. Many brain diseases, such as autism spectrum disorder, Alzheimer’s disease, and epilepsy, are linked to problems with AMPA receptors. Lipoic acid is a natural chemical that helps protect the brain. It does this by calming down swelling (inflammation) and stopping damage caused by harmful molecules. By keeping brain cells healthier, lipoic acid might help treat brain diseases by making sure AMPA receptors work properly [5, 6].

How Did We Test the Effects of Lipoic Acid On AMPA Receptors?

To study how lipoic acid affects AMPA receptors, we needed to pick one specific kind of cell. Instead of using real brain neurons, we used special lab-grown cells called HEK293T cells (Figure 2). These cells come from human tissue and are much easier to grow and control than real neurons. To make them act like neurons, we give the cells new instruction molecules (DNA or RNA) that teach them to build the same AMPA receptor gates found in brain cells. These instructions basically tell the cells to behave more like brain cells. After giving the cells 2 days in a warm incubator to complete this change, we checked if it worked by adding a colored protein. If the cells glow with color, we know the process was successful.

Neurons send electric-chemical messages via chemicals called neurotransmitters, which help these signals travel across a synapse. If neurons are damaged or the chemical environment around them changes, such as during disease or after injury, the flow of neurotransmitters can be disrupted. To see how lipoic acid changes the signals sent between neurons, we used a very sensitive electrical recording technique that allows us to measure the electrical current, which is the flow of ions inside a single AMPA receptor “gate”. We use a very thin glass tube called a micro-pipette. The micro-pipette is filled with a solution, and when it touches the cell membrane, a tight seal forms. Think of the cell as a small house: we gently make a window just big enough to peek in, so we can watch the “lights” (ion currents) turning on and off. Through this window, we measure how ions move through the AMPA receptor, letting us see exactly how active the cell is. This technique, which is called whole-cell patch clamp, helps us get accurate measurements of how the ion channels are working.

What Did We Discover About Lipoic Acid?

In our study, we applied the form of lipoic acid that the body naturally uses (called α-lipoic acid or α-LA), to the HEK293T cells and then used whole-cell patch clamp to see how α-LA affects AMPA receptors (Figure 3). We compared how much current normally flowed through the gates when the cells were given only glutamate, the brain’s usual key that opens AMPA receptors, vs. when they were given glutamate plus α-LA. We found that α-LA made the current smaller, meaning it weakened the response of the AMPA receptors.

We also discovered that α-LA worked best at a certain amount (14 micromolar), and it took only a small amount of α-LA to start seeing an effect (3.5–4 micromolar). We carefully kept the glutamate levels steady while adjusting the amount of α-LA, to see how the receptors reacted. We found that the AMPA receptors “turned off” faster when both glutamate and α-LA were present, compared to just glutamate. This means the receptors became less active twice as fast when exposed to α-LA. This is considered significant because this quicker shut-off shortens the time that ions like calcium flood into the cell, lowering the risk of overactivity that can contribute stress or even damage the neuron and lead to disease.

Conclusion

In this study, a type of lipoic acid was tested on AMPA receptor building blocks to test whether it could slow the gates down and stop too much calcium from rushing into the cell. Our results are important because lipoic acid is known for its ability to reduce inflammation and to protect brain cells from damage caused by Alzheimer’s disease, for example. In Alzheimer’s disease, AMPA receptors do not work properly, so studying lipoic acid could provide useful information that could help scientists develop new treatments or prevention methods. Since we do not know much about AMPA receptors yet, studying lipoic acid could improve our understanding of how they function. Although our experiments measured how lipoic acid quiets the electrical response of AMPA receptors in simplified lab cells, future studies must pinpoint exactly where and how lipoic acid binds to these receptors inside real neurons, which could lead to important findings about Alzheimer’s and other brain-related diseases.

Glossary

Neurons: ↑ Special brain and nerve cells that send and receive signals.

Neurotransmission: ↑ The brain’s “text messaging system”, where tiny signals travel between nerve cells.

Synapse: ↑ The tiny gap where two neurons meet and pass chemical messages.

Ions: ↑ Tiny charged particles, like sodium or calcium, that create the electrical part of nerve signals.

AMPA Receptor: ↑ A “gate” on neurons that opens to let ions in when glutamate arrives.

Glutamate: ↑ The brain’s main “go” chemical that starts many nerve signals.

Lipoic Acid: ↑ A natural compound that protects brain cells by calming swelling and reducing damage.

Neurotransmitter: ↑ A chemical messenger that carries signals from one neuron to another.

Whole-cell Patch Clamp: ↑ A lab tool that lets scientists gently “listen” to the tiny currents inside one cell.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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