Researchers collaborating across three institutions in Singapore managed to do what many before them have failed: to mass produce GABA neurons — those nerve cells acting as a brake on nerve signaling — from stem cells in the lab.
The new method, described in the study “Direct Induction and Functional Maturation of Forebrain GABAergic Neurons from Human Pluripotent Stem Cells,” recently published in the journal Cell Reports, will provide scientists studying epilepsy, as well as other psychiatric conditions, with an unlimited source of GABA neurons for studies of disease mechanisms and drug screening.
GABA-producing neurons are the main brake of nerve cell activity in the brain, acting to fine-tune processes by dampening the signaling by so-called excitatory neurons. Excitatory neurons, as the name implies, agitate the others, while inhibitory GABA neurons serve as moderators to calm them.
“Just like how a balance of yin and yang is needed in order to stay healthy, a balance of excitatory neurons and GABA neurons is required for normal brain function,” Dr. Alfred Sun, a Research Fellow at the National Neuroscience Institute and one of the first authors of the study alongside Qiang Yuan, a Duke-NUS Medical School PhD student, said in a news release.
Scientists studying both epilepsy and psychiatric conditions such as autism and schizophrenia have had high-quality human GABA neurons to study in the lab on their wish list, as this would allow them to study processes that are difficult to research in other ways.
But making these cells has turned out to be difficult, and progress has been hampered by complex protocols, poor yields, and long time frames.
Using human induced pluripotent stem cells, the study, also involving scientists from A*STAR’s Genome Institute of Singapore, managed to develop a method to produce GABA neurons in just one step. To do this, however, they had to go back in time, studying the genetic factors that are active when such neurons are born in the brain. Such factors act during development to tell early brain cells to become a GABA neuron, rather than some other type of cell.
Once they had identified the factors needed, the scientists used a trial and error approach to test many combinations of the factors to drive the pluripotent stem cells to become GABA neurons, essentially mimicking the process going on during brain development. Eventually, they succeeded in identifying just the right mix, producing GABA neurons looking and behaving like those in an adult brain.
“Our quick, efficient, and easy way to mass produce GABA neurons for lab use is a game changer for neuroscience and drug discovery. With increased recognition of the essential role of GABA neurons in almost all neurological and psychiatric diseases, we envisage our new method to be widely used to advance research and drug screening,” said Shawn Je, an assistant professor in the Neuroscience and Behavioral Disorders Program at Duke-NUS, and senior author of the study.