According to the CDC, about 3.4 million people are living with epilepsy nationwide. Epilepsy is the fourth most common neurological disorder and affects people of all ages. It is caused by a malfunction in brain cells and is usually treated with medicines that control or counteract the seizures. Now researchers at the Faculty of Health and Medical Sciences, University of Copenhagen and Rigshospitalet report they have identified the exact neurons that are most affected by epilepsy. The neurons may play a role in epileptogenesis, which is the gradual process by which a normal brain develops epilepsy.

Their findings, “Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis,” are published in the journal Nature Communications.

“Our findings potentially allow for the development of entirely new therapeutic approaches tailored towards specific neurons, which are malfunctioning in cases of epilepsy,” stated Konstantin Khodosevich, associate professor from the Biotech Research & Innovation Center (BRIC), Faculty of Health and Medical Sciences. “This could be a breakthrough in personalized medicine-based treatment of patients suffering from epileptic seizures.”

Using a single-cell transcriptomics approach in the human brain, the researchers identified large-scale changes in the transcriptome of the epileptic cortex that were distributed across multiple neuronal subtypes.

“To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects,” the researchers wrote.

This study is the first to investigate how every single neuron in the epileptic zone of the human brain is affected by epilepsy. The researchers have analyzed more than 117,000 neurons, which makes it the largest single cell dataset for a brain disorder published so far.

The researchers also identified those subtypes of principal and GABAergic interneurons as the most likely candidates for contributing to seizure triggering and propagation.

“By splitting the neurons into many thousands of single cells, we can analyze each of them separately. From this huge number of single cells, we can pinpoint exactly what neurons are affected by epilepsy. We can even make a scale from least to most affected, which means that we can identify the molecules with the most promising potential to be effective therapeutic targets,” noted Khodosevich.

Looking toward the future, the researchers’ next step is to study the neurons and how their functional changes contribute to epileptic seizures. The hope is to then find molecules that can restore epilepsy-related neuronal function back to normal and inhibit seizure generation.

“Future translational studies in mouse models and human tissue are necessary to resolve which of the identified pathways leads to seizure generation and propagation, and which rather represent the homeostatic plasticity of neuronal networks,” the researchers wrote.

“We show that the complexity of gene expression in epilepsy is much larger than previously known. It is not a matter of a handful or a few hundred genes changing. Our study proves that thousands of genes in different neurons change their expression in epilepsy. From these thousands of gene expression changes, we identified those that most likely contribute to epileptogenesis. Now it is time to prove it functionally,” concluded Khodosevich.

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