Clues to epilepsy in a dish
A new stem cell-based approach to studying epilepsy has yielded a surprising discovery about what causes one form of the condition, and may help in the search for better medicines to treat all kinds of seizure disorders.
The diagram opposite shows the process by which scientists can take skin cells from patients with epilepsy, convert them to stem cells, and then create neurons (brain nerve cells) from them. The induced neurons contain the same genetic mutation(s) carried by the patients.
The findings, reported by a team of scientists from the University of Michigan Medical School and colleagues, use a technique that could be called 'epilepsy in a dish'.
By turning skin cells of epilepsy patients into stem cells, and then turning those stem cells into neurons, or brain nerve cells, the team created a miniature testing ground for epilepsy. They could even measure the signals that the cells were sending to one another, through tiny portals called sodium channels.
In neurons derived from the cells of children who have a severe, rare genetic form of epilepsy called Dravet syndrome, the researchers report abnormally high levels of sodium current activity. They saw spontaneous bursts of communication and "hyperexcitability" that could potentially set off seizures. Neurons made from the skin cells of people without epilepsy showed none of this abnormal activity.
They report their results online in the Annals of Neurology, and have further work in progress to create induced pluripotent stem cell lines from the cells of patients with other genetic forms of epilepsy.
The new findings differ from what other scientists have seen in mice—demonstrating the importance of studying cells made from human epilepsy patients. Because the cells came from patients, they contained the hallmark seen in most patients with Dravet syndrome: a new mutation in SCN1A, the gene that encodes the crucial sodium channel protein called Nav1.1. That mutation reduces the number of channels to half the normal number in patients' brains.
'With this technique, we can study cells that closely resemble the patient's own brain cells, without doing a brain biopsy,' says senior author and team leader Jack M. Parent, M.D., professor of neurology at U-M and a researcher at the VA Ann Arbor Healthcare System. 'It appears that the cells are overcompensating for the loss of channels due to the mutation. These patient-specific induced neurons hold great promise for modelling seizure disorders, and potentially screening medications.'