Nav: Home

Scientists accidentally reprogram mature mouse GABA neurons into dopaminergic-like neurons

October 11, 2018

Attempting to make dopamine-producing neurons out of glial cells in mouse brains, a group of researchers instead converted mature inhibitory neurons into dopaminergic cells. Their findings, appearing October 11 in the journal Stem Cell Reports, reveal that--contrary to previous belief--it is possible to reprogram one mature neuron type into another without first reverting it to a stem-cell-like state.

"Initially, I was a little disappointed that we converted medium spiny neurons instead of glia," says first author Chun-Li Zhang, a professor of molecular biology at UT Southwestern Medical Center (@UTSWNews). "But when we realized the novelty of our results, we were kind of amazed. To our knowledge, changing the phenotype of resident, already-mature neurons has never been accomplished before."

Dopaminergic cells are important for controlling voluntary movement and emotions such as motivation and reward that drive behavior. They are often lost in movement disorders like Parkinson's disease. Many neuroscientists are interested in the therapeutic potential of creating new dopaminergic cells.

Zhang and his team attempted to induce the glia--cells surrounding neurons with protective and other functions--to morph inside live mouse brains. They injected a viral vector to express a cocktail of proteins into the striatum, a region of the brain rich in GABAergic neurons that help control muscle movement. The cocktail consisted of three transcription factors, NURR1, FOXA2, and LMX1A, which help decode genetic instructions for building dopaminergic neurons. The mice were also treated with valproic acid, which was previously shown to play a role in cell reprogramming.

The team targeted glial cells due to their ability to regenerate and multiply more readily than neurons, theoretically making them better therapeutic candidates. But when they looked at the brain slices of the injected mice, they found the glia unchanged. Instead, some GABAergic medium spiny neurons--cells that are directly controlled by dopaminergic neurons--had transformed.

The new cells appeared to behave more like native dopaminergic neurons, although they also retained residual features of the medium spiny neurons. They showed rhythmic activity and formed network connections similarly to dopaminergic cells, as the researchers discovered through electrode recordings and reporter assays.

Subsequent immunohistochemistry and reporter assays revealed that the new cells sprung from mature medium spiny neurons without passing through a proliferative progenitor stage.

"Our results offer a new perspective on neuronal plasticity," says Zhang. "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."

Zhang and his team next seek to address some of the limitations of their findings by clarifying the exact reprogramming mechanism and, of course, identifying the conditions that can reprogram glia into dopaminergic neurons, as they originally sought.

"We hope that the ability to change neuron identity will someday be directed to treat neurological diseases, including Parkinson's disease," says Zhang.
-end-
This research was funded by the Welch Foundation, the Mobility Foundation, the Michael J. Fox Foundation, the Decherd Foundation, the Pape Adams Foundation, Texas Institute for Brain Injury and Repair, Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration and the National Institutes of Health.

Stem Cell Reports, Zhang et al.: "Phenotypic reprogramming of striatal neurons into dopaminergic neuron-like cells in the adult mouse brain" https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(18)30389-8

Stem Cell Reports, published by Cell Press for the International Society for Stem Cell Research (@ISSCR), is a monthly open-access forum communicating basic discoveries in stem cell research, in addition to translational and clinical studies. The journal focuses on shorter, single-point manuscripts that report original research with conceptual or practical advances that are of broad interest to stem cell biologists and clinicians. Visit http://www.cell.com/stem-cell-reports. To receive Cell Press media alerts, please contact press@cell.com.

Cell Press

Related Neurons Articles:

How do we get so many different types of neurons in our brain?
SMU (Southern Methodist University) researchers have discovered another layer of complexity in gene expression, which could help explain how we're able to have so many billions of neurons in our brain.
These neurons affect how much you do, or don't, want to eat
University of Arizona researchers have identified a network of neurons that coordinate with other brain regions to influence eating behaviors.
Mood neurons mature during adolescence
Researchers have discovered a mysterious group of neurons in the amygdala -- a key center for emotional processing in the brain -- that stay in an immature, prenatal developmental state throughout childhood.
Astrocytes protect neurons from toxic buildup
Neurons off-load toxic by-products to astrocytes, which process and recycle them.
Connecting neurons in the brain
Leuven researchers uncover new mechanisms of brain development that determine when, where and how strongly distinct brain cells interconnect.
The salt-craving neurons
Pass the potato chips, please! New research discovers neural circuits that regulate craving and satiation for salty tastes.
When neurons are out of shape, antidepressants may not work
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medication for major depressive disorder (MDD), yet scientists still do not understand why the treatment does not work in nearly thirty percent of patients with MDD.
Losing neurons can sometimes not be that bad
Current thinking about Alzheimer's disease is that neuronal cell death in the brain is to blame for the cognitive havoc caused by the disease.
Neurons that fire together, don't always wire together
As the adage goes 'neurons that fire together, wire together,' but a new paper published today in Neuron demonstrates that, in addition to response similarity, projection target also constrains local connectivity.
Scientists accidentally reprogram mature mouse GABA neurons into dopaminergic-like neurons
Attempting to make dopamine-producing neurons out of glial cells in mouse brains, a group of researchers instead converted mature inhibitory neurons into dopaminergic cells.
More Neurons News and Neurons Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.