Featured Research

from universities, journals, and other organizations

Depressed Mice Reveal Critical Chemical Pathway For Treatment

Date:
February 8, 2008
Source:
Duke University Medical Center
Summary:
Blocking production of a single enzyme alleviates symptoms of depression and anxiety in mice that have low serotonin levels, researchers have found. Serotonin, a chemical that helps brain cells communicate with one another, is the target of the most successful anti-depressant medications. Low levels of serotonin are implicated in depression and many other psychiatric disorders, including increased anxiety, aggression and obsessive-compulsive disorder.

Blocking production of a single enzyme alleviates symptoms of depression and anxiety in mice that have low serotonin levels, Duke University Medical Center researchers have found.

Serotonin, a chemical that helps brain cells communicate with one another, is the target of the most successful anti-depressant medications. Low levels of serotonin are implicated in depression and many other psychiatric disorders, including increased anxiety, aggression and obsessive-compulsive disorder.

The Duke team created mice with a mutation in the gene for tryptophan hydroxylase 2 (Tph2), which helps make serotonin in the brain. An equivalent human mutation has been identified in some people with unipolar major depression. These patients often show resistance to treatment with SSRI antidepressant drugs.

Mice with the mutation had 80 percent less serotonin in their brains than normal mice and exhibited behavioral changes that mirror the symptoms of humans with low serotonin.

However, the study revealed a possible means for alleviating these symptoms. The drop in serotonin levels was accompanied by an increase in the activity of another enzyme, called glycogen synthase kinase 3 (GSK-3), which helps a cell respond to chemical signals, including serotonin.

Communication between cells operates much like a string of medieval signaling towers – a fire lighted in one tower alerts the next in the chain, quickly transmitting a message across far distances. The Duke researchers discovered that blocking one of these signaling towers, GSK-3, restored normal behavior in the mutant mice.

The findings appear in the January 29, 2008 edition of the Proceedings of the National Academy of Sciences. The study was funded by the National Institutes of Health, the Lennon Family Foundation, NARSAD and the Canadian Institutes of Health Research.

GSK-3 is well known in the pharmaceutical industry – many different psychiatric drugs block the enzyme, including lithium, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs).

The researchers tested the SSRI drug fluoxetine (Prozac) in the mutant mice, finding that short-term treatment relieved the animal's depressive symptoms and inhibited GSK-3 activity in the brain. The team is now evaluating the effects of long-term treatment with SSRI drugs.

They also prevented depression from developing by breeding mice with a mutation in the gene for GSK-3. "That GSK-3 is involved was expected. But the fact that removing one version of the GSK-3B gene reversed the behavior was quite surprising to us," said lead author Jean-Martin Beaulieu, Ph.D., now at Universitι Laval in Quebec. "This suggests that serotonin's effects on mood and aggression may be partly controlled through regulation of GSK-3 activity."

The dramatic drop in serotonin seen in the mice is caused by a single-letter difference in the spelling of a gene that has 200,000 letters of DNA code. This one-letter change is called a single nucleotide polymorphism, or SNP – a site where the DNA sequence of individuals differs by just one of four nucleotides (A, T, C or G). For example, some people may have G at a particular site, while others have an A. The SNP studied by the Duke researchers affects the Tph2 gene, built of some 100,000 nucleotide pairs.

The study also confirms that the Tph2 enzyme is critical for making brain serotonin, said Xiaodong Zhang, Ph.D., study co-author and an assistant professor at the Duke-NUS Graduate Medical School Singapore. The results imply that humans with this mutation may have serious deficits in brain serotonin, he said.

In addition to revealing new clues to serotonin signaling in the brain, the Tph2-mutant mice could also serve as an animal model of drug-resistant depression. The Duke researchers have patented the strain of mice used in the study, said senior study author Marc Caron, Ph.D., James B. Duke professor of cell biology.

"These animals may be one of the better models for preclinical studies," Caron said. "We now have an animal model that mimics many of the things you would expect of people that are depressed."

Collaborators on the study include Ramona Rodriguiz, Tatyana Sotnikova, Michael Cools, William Wetsel and Raul Gainetdinov, all of Duke.


Story Source:

The above story is based on materials provided by Duke University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Duke University Medical Center. "Depressed Mice Reveal Critical Chemical Pathway For Treatment." ScienceDaily. ScienceDaily, 8 February 2008. <www.sciencedaily.com/releases/2008/02/080207131854.htm>.
Duke University Medical Center. (2008, February 8). Depressed Mice Reveal Critical Chemical Pathway For Treatment. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2008/02/080207131854.htm
Duke University Medical Center. "Depressed Mice Reveal Critical Chemical Pathway For Treatment." ScienceDaily. www.sciencedaily.com/releases/2008/02/080207131854.htm (accessed October 21, 2014).

Share This



More Mind & Brain News

Tuesday, October 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

Newsy (Oct. 21, 2014) — A medical team has for the first time given a man the ability to walk again after transplanting cells from his brain onto his severed spinal cord. Video provided by Newsy
Powered by NewsLook.com
Portable Breathalyzer Gets You Home Safely

Portable Breathalyzer Gets You Home Safely

Buzz60 (Oct. 21, 2014) — Breeze, a portable breathalyzer, gets you home safely by instantly showing your blood alcohol content, and with one tap, lets you call an Uber, a cab or a friend from your contact list to pick you up. Sean Dowling (@SeanDowlingTV) has the details. Video provided by Buzz60
Powered by NewsLook.com
Your Birth Season Might Determine Your Temperament

Your Birth Season Might Determine Your Temperament

Newsy (Oct. 20, 2014) — A new study says the season you're born in can determine your temperament — and one season has a surprising outcome. Video provided by Newsy
Powered by NewsLook.com
Movies Might Desensitize Violence For Parents, Not Just Kids

Movies Might Desensitize Violence For Parents, Not Just Kids

Newsy (Oct. 20, 2014) — A study suggests that parents become desensitized to violent movies as well as children, which leads them to allow their kids to view violent films. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins