Stem cell-derived neurons stop seizures, improve cognitive function

Researchers at Texas A&M University are working on a better and permanent treatment for epilepsy, supported by a grant from the Department of Defense. Their results were published recently in the Proceedings of the National Academy of Sciences.

The research team is led by Ashok K. Shetty, a professor in the Department of Molecular and Cellular Medicine at the Texas A&M College of Medicine, associate director of the Institute for Regenerative Medicine and a research career scientist at the Olin E. Teague Veterans’ Medical Center, part of the Central Texas Veterans Health Care System.

About 3.4 million Americans, or 1.2 percent of the population, have active epilepsy. Although the majority respond to medication, between 20 and 40 percent of patients with epilepsy continue to have seizures even after trying multiple anti-seizure drugs. Even when the drugs do work, people may develop cognitive and memory problems and depression, likely from the combination of the underlying seizure disorder and the drugs to treat it.

Seizures are caused when the excitatory neurons in the brain fire too much and inhibitory neurons—the ones that tell the excitatory neurons to stop firing—aren’t as abundant or aren’t operating at their optimal level. The main inhibitory neurotransmitter in the brain is called GABA, short for gamma-Aminobutyric acid.

Over the last decade, scientists have learned how to create induced pluripotent stem cells from ordinary adult cells, like a skin cell. These stem cells can then be coaxed to become virtually any type of cells in the body, including neurons that use GABA, called GABAergic interneurons.

“What we did is transplant human induced pluripotent stem cell-derived GABAergic progenitor cells into the hippocampus in an animal model of early temporal lobe epilepsy,” Shetty said. The hippocampus is a region in the brain where seizures originate in temporal lobe epilepsy, which is also important for learning, memory and mood. “It worked very well to suppress seizures and even to improve cognitive and mood function in the chronic phase of epilepsy.”

Further testing showed that these transplanted human neurons formed synapses, or connections, with the host excitatory neurons. “They were also positive for GABA and other markers of specialized subclasses of inhibitory interneurons, which was the goal,” Shetty said. “Another fascinating aspect of this study is that transplanted human GABAergic neurons were found to be directly involved in controlling seizures, as silencing the transplanted GABAergic neurons resulted in an increased number of seizures.”

Shetty cautioned that these tests were early interventions after the initial brain injury induced by status epilepticus, which is a state of continuous seizures lasting more than five minutes in humans. The next step is to see if similar transplants would work for cases of chronic epilepsy, particularly drug-resistant epilepsy.

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