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.
The Stanford University School of Medicine consistently ranks among the nation's top 10 medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
Ranked as one of the best pediatric hospitals in the nation by U.S.News & World Report, Lucile Packard Children's Hospital at Stanford is a 272-bed hospital devoted to the care of children and expectant mothers. Providing pediatric and obstetric medical and surgical services and associated with the Stanford University School of Medicine, Packard Children's offers patients locally, regionally and nationally the full range of health-care programs and services — from preventive and routine care to the diagnosis and treatment of serious illness and injury. For more information, visit http://www.lpch.org.
Erin Digitale | EurekAlert!
Speed data for the brain’s navigation system
06.12.2016 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)
Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
07.12.2016 | Earth Sciences
07.12.2016 | Earth Sciences
07.12.2016 | Materials Sciences