When silence becomes deadly

Blocking electrical signaling in the entorhinal cortex leads to the death of neurons in this brain region, which could have implications for Alzheimer’s disease

When their electrical activity is artificially shut down, neurons in the entorhinal cortex of mice (in green) degenerate; the thread-like structures that connect them to the neighboring hippocampus retract, their endings forming club-like bulbs in the process. Image credit: Stacy Grunke and Joanna Jankowsky (CC BY 4.0)

Neurodegenerative conditions cause irreversible damage to the brain and have a devastating impact on quality of life. However, these diseases start gradually, meaning that the entire brain is not affected at once. For example, the initial signs of Alzheimer’s disease appear only in specific areas.

One of the first brain regions to degenerate in Alzheimer’s is the entorhinal cortex. In healthy individuals, entorhinal neurons send electrical signals to the hippocampus, a part of the brain important for memory and learning. During Alzheimer’s, hippocampal neurons also die off, leading to ‘shrinkage’ of this brain region and, ultimately, the memory problems that are a hallmark of the disease.

Many neurons in the developing brain require electrical input from other cells to survive – in other words, if they do not belong to an ‘active circuit’, they are eliminated. This is crucial for the connection between the entorhinal cortex and the hippocampus, where the circuit's development and maintenance require carefully controlled electrical activity. Abnormal electrical activity is also an early sign of diseases like Alzheimer’s, but how this relates to degeneration is still poorly understood.

By investigating these questions, Zhao, Grunke, Wood et al. uncovered a potential relationship between electrical activity and degeneration in the adult brain, long after the circuit between the hippocampus and the entorhinal cortex had matured.

Mice were genetically engineered so that their entorhinal cortex would carry a protein designed to silence electrical signaling. The communication between the entorhinal cortex and the hippocampus could therefore be shut off by activating the protein with an injected drug. Remarkably, within just a few days of silencing, cells from the entorhinal cortex started to die off.

Zhao, Grunke, Wood et al. went on to show that different silencing methods yielded the same results – in other words, the degeneration of cells from the entorhinal cortex was not linked to a particular method. This vulnerability to electrical inactivity was also unique to the entorhinal cortex: when neighboring parts of the brain were silenced, the nerve cells in these areas did not die as readily. Interestingly, in one of their experiments, Zhao, Grunke, Wood et al. found that electrical activity of neighboring nerve cells participated in killing the silenced neurons, suggesting that nerve cells in these brain areas might compete to survive.

Overall, this work highlights a direct link between electrical activity and nerve cell degeneration in a part of the brain severely affected by Alzheimer’s. In the future, Zhao, Grunke, Wood et al. hope that these results will pave the way to a better understanding of the biological mechanisms underpinning such neurodegenerative diseases.