Korean Research Team Identifies World's First Cause of Brain Neuron Excitation and Seizures

Research Team Including KAIST Professor Jeong Won-seok Uncovers Mechanism by Which Microglia Trigger Seizures When Removing Inhibitory Synapses

[Asia Economy Reporter Kim Bong-su] Domestic researchers have identified a new mechanism that causes an imbalance between excitation and inhibition in brain nerve cells. This discovery is expected to help understand and treat various brain neurological disorders such as seizures.

The Korea Advanced Institute of Science and Technology (KAIST) announced on the 2nd that Professor Jeong Won-seok and PhD candidate Park Jung-joo from the Department of Life Sciences have, for the first time, revealed the molecular mechanism by which inhibitory synapses (clusters of neurons) are eliminated by microglia (immune cells in the brain). They also demonstrated that excessive occurrence of this phenomenon can lead to increased excitability of nerve cells, causing brain disorders such as seizures. The research findings were published in the international journal EMBO Journal on the 20th of last month.

Synapses undergo repeated formation and elimination during brain development and learning. The research team had previously shown that non-neuronal cells such as astrocytes and microglia can engulf and remove unnecessary synapses of nerve cells. However, it was unknown which substances mark specific synapses to induce glial cells to remove them.

The team focused on phosphatidylserine, a phospholipid present in the cell membrane, which is selectively exposed on the surface of dying cells to induce immune cells to engulf them. They hypothesized that the molecular mechanism for removing dying cells could also apply to the selective removal of synapses. To test this, the researchers artificially exposed phosphatidylserine on the surface of nerve cells and studied whether specific synapses could be engulfed by glial cells.

They created an experimental mouse model in which the function of a protein called flippase, which continuously pulls phosphatidylserine from the cell surface inward to prevent its exposure on normal cell membranes, was selectively inhibited only in nerve cells. Surprisingly, they found that phosphatidylserine was selectively exposed only on the surface around the cell bodies of nerve cells, resulting in a selective decrease in inhibitory synapses without damage to the cell membrane or excitatory synapses. This mouse model also exhibited a disrupted excitation-inhibition balance in the brain region responsible for hearing, causing unusual seizure symptoms triggered by sound.

When microglia were artificially removed or a specific phagocytic receptor present in microglia was eliminated, excessive reduction of inhibitory synapses and seizure symptoms were prevented even if phosphatidylserine was exposed on the surface of nerve cells. This was the first demonstration that phosphatidylserine exposure on the cell membrane around nerve cell bodies can serve as a mechanism by which microglia selectively engulf inhibitory synapses through phagocytic receptors.

This discovery by the research team is the first to suggest that excitatory and inhibitory synapses can be removed by microglia through different mechanisms. It also proves that excessive removal of inhibitory synapses by microglia can be a new cause of excitation-inhibition imbalance in brain nerve cells.

A representative of the research team stated, "Abnormal changes in the number of inhibitory synapses are highly correlated with the prevalence of various brain disorders such as seizures, autism spectrum disorder, schizophrenia, and dementia. Regulating the phenomenon of microglia engulfing inhibitory synapses in various brain neurological disorders caused by disrupted excitation-inhibition balance will be a new strategy for treating these diseases."

This content was produced with the assistance of AI translation services.