Researchers from University of Texas (UT) Southwestern Medical Center were attempting to transform supporting brain cells into neurons when, instead, they reprogrammed mature inhibitory neurons into a different type of neuron that creates the neurotransmitter lost in Parkinson’s disease. When the scientists unexpectedly transformed mature inhibitory striatal neurons into dopamine-producing neurons, they realized that the brain’s neurons are more changeable in adulthood than previously thought. This discovery reveals the possibility of changing mature neurons from one kind to another without relying on stem cells. The study has been published in Stem Cell Reports.
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, said corresponding author Dr. Chun-Li Zhang, a W.W. Caruth, Jr. Scholar in Biomedical Research and Professor of Molecular Biology at UT Southwestern Medical Center. “To find that we could manipulate neurons to change their identity in adulthood was truly unexpected.” Insights (such as this) into neuronal plasticity and cell identity maintenance may someday lead to therapeutic strategies for treating neurological diseases through the reprogramming of local neurons.
Dr. Zhang said:
Initially, I was a little disappointed that we altered the properties of medium spiny neurons and not the supporting glial cells we were targeting. 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.
GABA
In movement disorders like Parkinson’s disease, the neurotransmitter dopamine is lost. That is why 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 mature medium spiny neurons that changed their identities in this study usually produce GABA. GABA is an inhibitory neurotransmitter that targets other neurons throughout the adult brain. Levels of the neurotransmitters GABA, dopamine, and others need to exist in a delicate balance in the brain for proper function. Meaning that since 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 Study
Using a viral vector – a tool commonly used by molecular biologists to deliver genetic material into cells – Dr. Zhang and his team administered a cocktail of genes expected to encourage reprogramming to live mouse brains. They were attempting to induce the glia – cells that encircle neurons to provide support, insulation, and protection – to change into dopamine-producing neurons.
The cocktail was injected into a region of the brain rich in GABA-producing medium spiny neurons known to help control motor skills called the striatum. Dopamine-producing neurons are normally located elsewhere in the brain but send long connections to control the medium spiny neurons in the striatum.
The Results
At first, the researchers saw new dopamine neurons and thought the glia had converted, but then many rounds of cell lineage testing revealed that the glia remained unchanged. “We got the new cells we wanted,” Dr. Zhang said. “But, they did not originate from glial cells.”
To understand what had happened they conducted in-depth follow-up experiments that confirmed the team’s suspicion: 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.
Dr. Zhang said:
Rather than originating from glia, the new dopamine cells came from local, existing mature neurons without passing through a stem cell state. This is a mature cell-to-mature cell transformation.
Conclusion
The laboratory’s goal now is to characterize the cells and their genetics in more detail. They are currently seeking to clarify the exact reprogramming mechanism and, of course, identifying the conditions that can reprogram glia into dopaminergic neurons, as they originally sought.
Dr. Zhang concludes:
Our results offer a new perspective on neuronal plasticity. We traditionally think of mature cell identity and function as fixed, but our findings suggest that they are more dependent on biochemical factors in their environment than we thought. This could mean that no cell type is fixed even for a functional, mature neuron. We hope that the ability to change neuron identity will someday be directed to treat neurological diseases, including Parkinson’s disease.
