Reprogramming mature mouse GABA neurons into dopaminergic neurons

Researchers attempting to transform supporting brain cells into neurons instead reprogrammed mature inhibitory neurons into a different type of neuron that creates the neurotransmitter lost in Parkinson's disease.

The study, published in Stem Cell Reports, reveals the possibility of changing mature neurons from one kind to another without relying on stem cells, contrary to the prevailing view.

The mouse study indicates that the brain's neurons are more changeable in adulthood than previously thought, said corresponding author. The long-held belief was that a neuron's identity was sealed well before adulthood and that one kind of neuron could not morph into another variety, the author added.

"Initially, I was a little disappointed that we altered the properties of medium spiny neurons and not the supporting glial cells we were targeting," the senior author said. "But when we realized the novelty of our results, we were amazed. To our knowledge, changing the identity of resident and mature neurons had never been accomplished."

Because the neurotransmitter dopamine is lost in movement disorders like Parkinson's disease, many neuroscientists are interested in the possibility of someday creating new dopamine-producing neurons. Dopaminergic cells are important for controlling voluntary movement and emotions such as motivation and reward that drive behavior, the explained.

For proper function, levels of the neurotransmitters GABA, dopamine, and others need to exist in a delicate balance in the brain, the author said. Because dopamine is involved in reward behavior, including addictive behaviors, any potential treatment to increase dopamine levels would also need a way to keep the levels of other neurotransmitters in balance, the author added.

The mature medium spiny neurons that changed their identities in this study usually produce GABA, an inhibitory neurotransmitter that targets other neurons throughout the adult brain, the author explained.

The team used a viral vector - a tool commonly used by molecular biologists to deliver genetic material into cells - to administer a cocktail of genes expected to encourage reprogramming to live mouse brains in an attempt to induce the glia to change into dopamine-producing neurons. Glia - from the Greek word for "glue" - are cells that encircle neurons to provide support, insulation, and protection.

The cocktail was injected into the striatum, a region of the brain rich in GABA-producing medium spiny neurons known to help control motor skills. Dopamine-producing neurons are normally located elsewhere in the brain but send long connections to control the medium spiny neurons in the striatum, the author said.

The researchers initially saw new dopamine neurons and thought the glia had converted. However, many rounds of cell lineage testing revealed that the glia remained unchanged.

"We got the new cells we wanted," the senior author said. "But, they did not originate from glial cells."

The unexpected results led to intense follow-up experiments that confirmed the team's suspicion that the new cells were directly transformed from mature GABA neurons. The new cells were more like dopamine-containing neurons, despite retaining some traits of the original cells, the author said, adding that characterizing the cells and their genetics in more detail is the laboratory's current goal.

"Rather than originating from glia, the new dopamine cells came from local, existing mature neurons without passing through a stem cell state," the senior author said. "This is a mature cell-to-mature cell transformation."

https://www.utsouthwestern.edu/newsroom/articles/year-2018/mouse-neurons.html