Learning How Gene Mutations Contribute to Epilepsy
Published December 2020 | Progress in Neurobiology
Scientists still do not fully understand how epilepsy develops. “This lack of knowledge has limited the development of epilepsy prevention therapies in patients at risk for developing the disease, such as following genetic mutations, brain tumor, stroke, head injury or brain infection,” says Steve Danzer, PhD, Department of Anesthesia.
Yet over the past decade, it has become clearer that mutations in genes regulating the mTOR pathway (a central regulator of metabolism and physiology) are one significant cause of epilepsy. Epilepsy-causing mutations in these genes may affect small regions of the brain or an entire brain hemisphere.
Focusing upon mTORopathies, a class of genetic epilepsies that develop in children, a research team led by Danzer and first author Candi LaSarge, PhD, developed a novel transgenic mouse model of epilepsy and used cutting-edge technology such as optogenetic silencing of abnormal neurons to better understand how gene deletions impact brain excitability and inhibitory cells.
“Children have gene mutations in variable numbers of brain cells, and we modeled this in mice,” Danzer explains.
The researchers deleted the gene Pten, a negative regulator of mTOR, from 0 to 40% of hippocampal granule cells. Low numbers of knockout cells led to subtle increases in brain excitability and occasional focal seizures, while more deletions reduced the number of protective (inhibitory) brain cells and caused epilepsy characterized by generalized seizures. These results suggest that “pro-epileptogenic changes begin in the brains of children with mTOR mutations before clinical disease is evident,” Danzer says. “It may be possible to target these preclinical changes to prevent epilepsy.”
Co-authors presented their findings at a conference in Nice, France, in October 2021. Meanwhile, NIH-supported follow-up studies are ongoing to identify secondary changes that convert sub-clinical epilepsy to clinical epilepsy, with a particular focus on ways to protect the inhibitory system from secondary damage caused by mTOR mutant neurons.
