Featured Research

from universities, journals, and other organizations

Cognitive dysfunction reversed in mouse model of Down syndrome

Date:
November 19, 2009
Source:
Stanford University Medical Center
Summary:
At birth, children with Down syndrome aren't developmentally delayed. But as they age, these kids fall behind. Memory deficits inherent in Down syndrome hinder learning, making it hard for the brain to collect experiences needed for normal cognitive development. Scientists have now demonstrated a possible new approach to slowing the inevitable progression of cognitive decline found in Down syndrome.

Laboratory mouse.
Credit: iStockphoto

At birth, children with Down syndrome aren't developmentally delayed. But as they age, these kids fall behind. Memory deficits inherent in Down syndrome hinder learning, making it hard for the brain to collect experiences needed for normal cognitive development.

Now, findings from the Stanford University School of Medicine and Lucile Packard Children's Hospital shed light on the neural basis of memory defects in Down syndrome and suggest a new strategy for treating the defects with medication. The study, which was conducted in mice, is the first to show that boosting norepinephrine signaling in the brains of mice genetically engineered to mimic Down syndrome improves their cognition. Norepinephrine is a neurotransmitter that nerve cells use to communicate.

"If you intervene early enough, you will be able to help kids with Down syndrome to collect and modulate information," said Ahmad Salehi, MD, PhD, the primary author of the study, which will be published Nov. 18 in Science Translational Medicine. "Theoretically, that could lead to an improvement in cognitive functions in these kids." Salehi, a research health science specialist at the Veterans Affairs Palo Alto Health Care System, was a senior scientist at the School of Medicine when the study was conducted.

Down syndrome is a genetic disorder caused by an extra copy of chromosome 21. Using a mouse model, Salehi and his colleagues are examining exactly how the brain malfunctions in Down syndrome. "Cognition doesn't fail in every aspect; it's failing in a structure-dependent fashion," he said.

For instance, people with Down syndrome struggle to use spatial and contextual information to form new memories, a function that depends on the hippocampus part of the brain. As a result, they have trouble with learning to navigate complex environments such as a new neighborhood or a shopping mall. But they're much better at remembering information linked to colors, sounds or other sensory cues because such sensory memories are coordinated by a different brain structure, the amygdala.

Salehi and his colleagues looked at what could be causing the problems in the hippocampus. Normally, as contextual or relational memories are formed, hippocampal neurons receive norepinephrine from neurons in another part of the brain, the locus coeruleus. The researchers showed that, like humans with Down syndrome, the mice in their experiments experienced early degeneration of the locus coeruleus.

When the locus coeruleus broke down in the study's mice, the animals failed at simple cognitive tests that required them to be aware of changes in the milieu: For instance, the genetically engineered mice, when placed in the strange environment of an unknown cage, did not build nests. That contrasts with normal mice, which typically build nests in such circumstances.

However, by giving norepinephrine precursors to the mice with the Down-syndrome-like condition, the researchers could fix the problem. Only a few hours after they got the drugs, which were converted to norepinephrine in the brain, these mice were just as good at nest-building and related cognitive tests as normal mice. Direct examination of neurons in the hippocampus of the genetically altered mice showed that these cells responded well to norepinephrine.

"We were very surprised to see that, wow, it worked so fast," Salehi said. The drugs' effect also wore off relatively quickly, he added.

Enhancement of norepinephrine signaling has been explored for other neurological conditions. Some of the drugs already on the market for depression and attention deficit hyperactivity disorder target the norepinephrine system; Salehi hopes the new results will spur tests of these drugs for Down syndrome.

Other studies of drug therapies for Down syndrome have targeted a different neurotransmitter, acetylcholine, which also acts at the hippocampus. Based on his team's new findings, Salehi said the ideal medication regimen for improving cognition in Down syndrome will likely improve both norepinephrine and acetylcholine signals.

The new study also provides the first direct link between locus coeruleus breakdown in Down syndrome and a specific gene. People with Down syndrome have an extra copy of a gene called APP on their extra chromosome 21. Other researchers have linked APP to Alzheimer's disease, another disorder in which spatial orientation and memory formation go awry. Salehi and colleagues previously linked APP to the breakdown of neurons that make acetylcholine in these mice.

Salehi's results give "a ray of hope and optimism for the Down syndrome community for the future," said Melanie Manning, MD, director of the Center for Down Syndrome at Lucile Packard Children's Hospital. Manning was not a part of Salehi's research team. "It's very exciting," she said. "We still have a long way to go, but these are very interesting results."

Salehi's collaborators at Stanford included life-science research assistants Mehrdad Faizi, PhD, Janice Valletta and R. Takimoto-Kimura; research associates Damien Colas, PhD, and Alexander Kleschevnikov, PhD; Jessenia Laguna, visiting fellow; Mehrdad Shamloo, PhD, senior research scientist; and former director of the Stanford Institute for Neuro-Innovation & Translational Neurosciences William Mobley, MD, PhD, who is now at the University of California-San Diego. Mobley had also been director of Packard Children's Center for Down Syndrome.

The research was funded by grants from the National Institutes of Health, the Larry L. Hillblom Foundation, the Down Syndrome Research and Treatment Foundation, the Thrasher Research Fund, Adler Foundation and the Alzheimer Association. The team has filed a patent application related to the research.


Story Source:

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


Cite This Page:

Stanford University Medical Center. "Cognitive dysfunction reversed in mouse model of Down syndrome." ScienceDaily. ScienceDaily, 19 November 2009. <www.sciencedaily.com/releases/2009/11/091118143207.htm>.
Stanford University Medical Center. (2009, November 19). Cognitive dysfunction reversed in mouse model of Down syndrome. ScienceDaily. Retrieved October 1, 2014 from www.sciencedaily.com/releases/2009/11/091118143207.htm
Stanford University Medical Center. "Cognitive dysfunction reversed in mouse model of Down syndrome." ScienceDaily. www.sciencedaily.com/releases/2009/11/091118143207.htm (accessed October 1, 2014).

Share This



More Health & Medicine News

Wednesday, October 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Some Positive Ebola News: Outbreak 'Contained' In Nigeria

Some Positive Ebola News: Outbreak 'Contained' In Nigeria

Newsy (Sep. 30, 2014) The CDC says a new case of Ebola has not been reported in Nigeria for more than 21 days, leading to hopes the outbreak might be nearing its end. Video provided by Newsy
Powered by NewsLook.com
UN Ebola Mission Head: Immediate Action Is Crucial

UN Ebola Mission Head: Immediate Action Is Crucial

AFP (Sep. 30, 2014) The newly appointed head of the United Nations Mission for Ebola Emergency Response (UNMEER), Anthony Banbury, outlines operations to tackle the virus. Duration: 00:39 Video provided by AFP
Powered by NewsLook.com
CDC Confirms First Case of Ebola in US

CDC Confirms First Case of Ebola in US

AP (Sep. 30, 2014) The CDC has confirmed the first diagnosed case of Ebola in the United States. The patient is being treated at a Dallas hospital after traveling earlier this month from Liberia. (Sept. 30) Video provided by AP
Powered by NewsLook.com
New Breast Cancer Drug Extends Lives In Clinical Trial

New Breast Cancer Drug Extends Lives In Clinical Trial

Newsy (Sep. 30, 2014) In a clinical trial, breast cancer patients lived an average of 15 months longer when they received new drug Perjeta along with Herceptin. 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