Challenging Parkinson's dogma

October 24, 2012

Scientists may have discovered why the standard treatment for Parkinson's disease is often effective for only a limited period of time. Their research could lead to a better understanding of many brain disorders, from drug addiction to depression, that share certain signaling molecules involved in modulating brain activity.

A team led by Bernardo Sabatini, Takeda Professor of Neurobiology at Harvard Medical School, used mouse models to study dopamine in the , a region of the brain involved in both movement and learning. In people, these neurons release dopamine, a that allows us to walk, speak and even type on a keyboard. When those cells die, as they do in Parkinson's patients, so does the ability to easily initiate movement. Current Parkinson's drugs are precursors of dopamine that are then converted into dopamine by cells in the brain.

The flip side of dopamine dearth is dopamine hyperactivity. Heroin, cocaine and rev up or mimic , ultimately reinforcing the learned reward of drug-taking. Other conditions such as obsessive-compulsive disorder, Tourette syndrome and even schizophrenia may also be related to the misregulation of dopamine.

In the October 11 issue of Nature, Sabatini and co-authors Nicolas Tritsch and Jun Ding reported that midbrain dopamine neurons release not only dopamine but also another neurotransmitter called GABA, which lowers . The previously unsuspected presence of GABA could explain why restoring only dopamine could cause initial improvements in Parkinson's patients to eventually wane. And if GABA is made by the same cells that produce other neurotransmitters, such as depression-linked serotonin, similar single-focus treatments could be less successful for the same reason.

"If what we found in the mouse applies to the human, then dopamine's only half the story," said Sabatini.

The surprising GABA story began in the Sabatini lab with a series of experiments designed to see what happens when cells release dopamine. The scientists used optogenetics, a powerful technique that relies on genetic manipulation to selectively sensitize cells to light. In laboratory dishes, researchers tested brain tissue from mice engineered to show activity in dopamine neurons. Typically in such experiments, other neurotransmitters would be blocked in order to highlight dopamine, but Tritsch, a postdoctoral fellow in the Sabatini lab, decided instead to keep the cell in as natural a state as possible.

When Tritsch activated the dopamine neurons and examined their effects on striatal neurons, he naturally expected to observe the effects of dopamine release. Instead, he saw rapid inhibition of the striatal neurons, making it clear that another neurotransmitter – which turned out to be the quick-acting GABA – was at work. This was so unusual that the team launched a series of experiments to confirm that GABA was being released directly by these dopamine neurons.

A standard way to detect GABA is to look for vesicular GABA transporter, or VGAT, a protein that packages and carries GABA into neurotransmitter vesicles. The scientists silenced the gene that makes VGAT in mice and found that the dopamine neurons released GABA even in the absence of VGAT.

The researchers then tested other transporters, zeroing in on one that ferries dopamine and a variety of other neurotransmitters. For reasons they don't yet understand, this protein – the vesicular monoamine transporter – also shuttles GABA.

"What makes this important now is that every manipulation that has targeted dopamine by targeting the vesicular monoamine transporter has altered GABA as well. And nobody's paid any attention to it," said Sabatini. "Every Parkinsonian model that we have in which we've lost dopamine has actually lost GABA, too. So we really have to go back now and think: Which of these effects are due to loss of GABA and which are due to loss of dopamine?"

Anatol Kreitzer, an assistant investigator at the Gladstone Institute of Neurological Disease in San Francisco, who was not involved in the research, called the findings remarkable.

"It was totally unexpected," said Kreitzer, who is also an assistant professor of physiology and neurology at the University of California, San Francisco. "At the molecular level, nobody really expected dopamine neurons to be releasing significant amounts of GABA. At the functional level, it's surprising that this major modulator of plasticity in the brain, which is so critical for Parkinson's, for learning and rewards, and for other psychiatric illnesses, can also release GABA. That raises a question as to what role GABA has."

GABA can very quickly change the electrical state of cells, inhibiting their activity by making them less excitable. Sabatini wonders if the loss of GABA in dopamine neurons could explain why hyperactivity is sometimes seen after chronic loss of these neurons.

The next challenge will be to explore whether other neurons that express the vesicular monoamine transporter also release GABA in addition to neurotransmitters such as serotonin and noradrenaline.

"These findings highlight how little we actually know about the most basic features of cell identity in the brain," said Sabatini.

Tritsch said what started out as a straightforward project to understand dopamine quickly changed direction, with lots of starts and stops on the way to some exciting new findings.

"It can be nice to come up with a hypothesis, test it, verify it, and have everything fall into place," he said. "But biology rarely works that way."

Explore further: Study shows how neurons interact, could lead to new treatment for addiction

Related Stories

Study shows how neurons interact, could lead to new treatment for addiction

January 18, 2012
Harvard scientists have developed the fullest picture yet of how neurons in the brain interact to reinforce behaviors ranging from learning to drug use, a finding that might open the door to possible breakthroughs in the ...

Discovery of brain's natural resistance to drugs may offer clues to treating addition

March 8, 2012
A single injection of cocaine or methamphetamine in mice caused their brains to put the brakes on neurons that generate sensations of pleasure, and these cellular changes lasted for at least a week, according to research ...

Study shines light on brain mechanism that controls reward enjoyment

March 21, 2012
What characterizes many people with depression, schizophrenia and some other mental illnesses is anhedonia: an inability to gain pleasure from normally pleasurable experiences.

Dopamine controls formation of new brain cells

April 8, 2011
(PhysOrg.com) -- A study of the salamander brain has led researchers at Karolinska Institutet to discover a hitherto unknown function of the neurotransmitter dopamine. In an article published in the prestigious scientific ...

Recommended for you

Hibernating ground squirrels provide clues to new stroke treatments

November 17, 2017
In the fight against brain damage caused by stroke, researchers have turned to an unlikely source of inspiration: hibernating ground squirrels.

Age and gut bacteria contribute to multiple sclerosis disease progression

November 17, 2017
Researchers at Rutgers Robert Wood Johnson Medical School published a study suggesting that gut bacteria at young age can contribute to multiple sclerosis (MS) disease onset and progression.

Molecular guardian defends cells, organs against excess cholesterol

November 16, 2017
A team of researchers at the Harvard T. H. Chan School of Public Health has illuminated a critical player in cholesterol metabolism that acts as a molecular guardian in cells to help maintain cholesterol levels within a safe, ...

Prototype ear plug sensor could improve monitoring of vital signs

November 16, 2017
Scientists have developed a sensor that fits in the ear, with the aim of monitoring the heart, brain and lungs functions for health and fitness.

Ancient enzyme could boost power of liquid biopsies to detect and profile cancers

November 16, 2017
Scientists are developing a set of medical tests called liquid biopsies that can rapidly detect the presence of cancers, infectious diseases and other conditions from only a small blood sample. Researchers at The University ...

FDA to crack down on risky stem cell offerings

November 16, 2017
U.S. health authorities announced plans Thursday to crack down on doctors pushing stem cell procedures that pose the gravest risks to patients amid an effort to police a burgeoning medical field that previously has received ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.