Eric Wang, Senior Photographer

A recent study by researchers at the Yale School of Medicine found that mice injected with similar gene mutations as humans who have some severe forms of epilepsy also exhibited very similar brain malformations as the humans.

The researchers investigated two severe epilepsy disorders that result from two neurodevelopmental disorders called focal cortical dysplasia and tuberous sclerosis complex. These severe forms of biological epilepsy appear in humans shortly after birth, leading to sudden recurrent seizures and brain damage. These forms of severe epilepsy are not easily treatable with normal anti-epilepsy medications. The similar brain malformations from the mutations in both the human and mice brains helped the scientists identify the protein, called HCN4, and the molecular pathway, called mTOR, that are key factors in causing these epilepsies, thereby helping them get closer to finding treatments for the conditions.

“About 35 to 40 perecent of patients with epilepsy are resistant to medication,” Dennis Spencer, an expert in Epilepsy Surgery at the Yale School of Medicine, told the News. “[Epilepsy is] very heterogeneous and so many patients who have epilepsy are resistant to medication and the medications that are used today are also quite heterogeneous.”

Dennis explained that, due to the heterogeneous nature of the different types of epilepsy, scientists did not know what causes these two specific severe forms of epilepsy. According to Angélique Bordey, professor of Neurosurgery and Cellular and Molecular Physiology at the School of Medicine and corresponding author of the study, it was also not known why many people with these particular forms of the disease were resistant to normal anti-epilepsy medications.

Bordey and her team worked to replicate the genetic mutations that cause these severe forms of epilepsy in the brains of mice for the experiment. They did this by replicating the mutations in the mice’s brains while they were still in the womb. After birth, the animals displayed similar brain malformations to people with focal cortical dysplasia and tuberous sclerosis complex.

“The first thing we looked at is whether we reproduced the human pathology,” Bordey told the News. “One characteristic of the human pathologies is that the cells are misplaced and they usually migrate.”

In order to search for the pathologies or malformations, the researchers looked at different sections of the brain and, using confocal microscopes, detected fluorescent cells affected by the mutations. Once the pathologies were identified in the mice, the research team evaluated the size of the cells within these malformations, which are usually much bigger than normal cells. They then observed that these pathologies in mice were very similar to the pathologies found in humans with severe forms of epilepsy. 

The researchers found that the mutations associated with the two neurodevelopmental disorders were linked to a molecular pathway called mTOR that plays a large role in cell growth. They concluded that the pathway is responsible for the generation of epilepsy seizures. They also identified how a specific protein or ion channel, known as HCN4, is a key aspect of allowing seizures to happen. Once the HCN4 channel was prevented from opening in a mouse’s brain, the seizures stopped.

Lena Nguyen, a postdoctoral fellow at the School of Medicine and one of the contributors to the experiment, told the News that the group plans to continue their work on this research area of epilepsy.

“We want to investigate the immediate connection between [mTOR] signaling pathway and the [HCN4] channel,” Nguyen said. “The second more overall step is how can we translate this into a treatment.”

Bordey estimates that Phase 1 trials of gene therapy to address these forms of epilepsy in humans could begin as soon as 2023.

The researchers hope that using gene therapy to treat these disorders could help decrease the number of seizures a person has over time.

This research was published by Science Translational Medicine and followed another study on epilepsy by the same group of scientists published in February.


Alvaro Perpuly | alvaro.perpuly@yale.edu