Neuroscientists from the University of Michigan created neurons from the skin of patients with Dravet syndrome (a severe form of epilepsy) and found a putative cause of seizures. The study, published in the journal Annals of Neurology, is the first one that used human, patient-derived neurons and contradicts previous studies in mice offering a new mechanism of a sub-type of epilepsy and may help in the search for therapies against many seizure-related diseases.
Epilepsy is a neurological disease that effects 1-2% of the population worldwide and is characterized by spontaneous, unanticipated seizures and epileptic spikes. Epilepsy’s onset is usually at infancy, but new cases can develop in the elderly. Causes can be genetic mutations, developmental defects, brain injury and others. Dravet syndrome is a type of epilepsy that begins in infancy and has no cure.
So far, scientists have studied Dravet Syndrom with transgenic mouse models and in vitro systems that provided useful information, but it was not certain whether they recapitulated the human neurons. To create a more physiological tool to study epilepsy, the group of Jack M. Parent, M.D., professor of neurology in Michigan University, created patient-specific neurons by using the induced pluripotent stem cell (iPSC) technique. In this method, scientists take skin cells from patients, transform them into pluripotent (the type of embryonic cells that can become most of the types of cells of our body) and differentiate them into a cell type of their choice. The resulting human cells in culture, neurons in this case, contain the gene mutations observed in the original patient genetic background, and therefore constitute a great tool to study the disease.
The research team created iPSC forebrain neurons (the affected cells that cause the disease) from skin of two 7-year-old Dravet syndrome patients with specific mutations in the SCN1A gene. Patients with mutations in SCN1A have a malfunctioned sodium channel, a pore on the neurons’ membrane which allows sodium to come in and out and create a necessary flow of ions for the neuron’s electrical properties.
The researchers found that the patient-derived neurons were constantly hyper active and had two or three times increased sodium current compared to controls. This contradicts with what scientists knew so far from experiments in mice with seizures or in in vitro systems where the opposite, decreased sodium current and reduced channel activity, was observed. Because these neurons are human and come from the exact genetic background of patients, “we can study cells that closely resemble the patient’s own brain cells, without doing a brain biopsy,” says Parent, who led the study.
This increased burst of activity is potentially the cause of seizures as neurons made from healthy controls did not exhibit such hyper activity. The experiments also recapitulate the mechanism in Dravet syndrome patients who do have their first seizures until several months after birth, as the hyperactivity in culture was observed only in mature neurons. “It appears that the cells are overcompensating for the loss of channels due to the mutation.”
The iPSC neurons made in this study can now be used to study further the mechanism as well as other types of epilepsy. Since they are derived from the patient, they can also be used to test new antiepileptic medications, a useful development because Dravet patients’s seizures do not respond to therapies and are in danger of sudden unexplained death in epilepsy (SUDEP) which accounts for 7-17% of deaths among epileptic individuals.