ARTICLE IN BRIEF
Investigators reported that when Ts65Dn mice were treated with a combination of drugs that restored norepinephrine concentrations in the hippocampus, learning and memory deficits associated with impaired hippocampal function were alleviated.
Boosting brain levels of norepinephrine improves cognition in a mouse model of Down syndrome (DS), raising the possibility that a similar treatment in humans could improve mental functioning in affected individuals, according to a study by California researchers.
The paper marks the third report in the past three years to reveal distinct pathways, each of them appearing to play a critical role, in the cognitive functioning of trisomal mice bred to have three copies of a fragment of mouse chromosome 16. With one clinical trial already underway and another planned, researchers said the field is in the midst of a “revolution.”
Because many of the drugs being tested are already approved for other indications, however, researchers expressed great concern about the risk of prescribing them to people with DS before clinical trials establishing their safety and efficacy for the disorder are completed.
The new study, published online Nov. 18 in the journal Science Translational Medicine, linked learning and memory defects in trisomic mice to neuronal degeneration in the locus coeruleus. The locus coeruleus normally produces the norepinephrine necessary for the hippocampus to form contextual or relational memories, which are necessary to recognize a novel environment or a location in a maze. The researchers showed that levels of the neurotransmitter were indeed lower in the hippocampus in genetically modified mice compared to controls.
When Ts65Dn mice were treated with a combination of drugs that restored norepinephrine concentrations in the hippocampus, learning and memory deficits associated with impaired hippocampal function were alleviated, as measured by tests of nest-building in novel environments and the recollection of adverse stimuli in mazes.
The senior author of the new study said he was surprised to see that raising norepinephrine levels in the brain improved cognitive functioning in the Ts65Dn mice within hours. “We were surprised to see that it worked so fast,” said Ahmad Salehi, MD, PhD, a research health science specialist at the Veterans Affairs Palo Alto Health Care System.
To deliver norepinephrine to the mouse brains, Dr. Salehi and colleagues administered its precursor by IP injection, l-threo-dihydroxyphenylserine (l-DOPS), which traverses the blood-brain barrier. They avoided the unwanted effects of norepinephrine outside the CNS by co-administering carbidopa, which inhibits the conversion of l-DOPS to norepinephrine but cannot pass through the blood-brain barrier.
The paper also showed that having three copies of the amyloid precursor protein (App) gene in the Ts65Dn mice is necessary for the degeneration of the locus coeruleus. When a variant of the Ts65Dn was created with only two copies of the App gene, locus coeruleus neurons remained intact, as indicated by staining for tyrosine.
Commenting on the study, Alberto Costa, MD, PhD, associate professor of medicine and neuroscience at the University of Colorado Denver School of Medicine in Aurora, said: “It was really well done work, and a strong contribution to the field. They not only were able to reverse the phenotype, but were also able to come up with a genetic cause of it, the over-expression of the gene for App.”
Last year, Dr. Costa published a paper in Neuropsychopharmacology revealing that the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine rescues performance deficits of the Ts65Dn mouse on a fear conditioning test. Dr. Costa is now leading a clinical trial of memantine based on his 2008 study in mice, and expects to publish the findings later this year. He noted that lithium is also being studied as a tool for improving cognition in patients with DS. “The field is actually in the middle of what could be a real revolution,” Dr. Costa said.
In 2007, another group published a paper in Nature Neuroscience showing that gamma-aminobutyric acid receptor A (GABA-A) antagonists, given at non-epileptic doses to the mouse model of DS for a period of weeks, resulted in persistent cognitive gains.
Meanwhile, trials of GABA-A antagonists for DS should enter the clinic in the new year, said Craig C. Garner, PhD, professor of psychiatry and behavioral sciences and co-director of the Center for Research and Treatment of Down Syndrome at Stanford University.
“The concept seems simple: take drugs with a history of being used in man and begin a human trial,” he said. “I thought that three years ago when we first identified GABA-A as a target. But it's a long road from finding a class of drugs that might work to going through all the safety and efficacy studies.”
Despite the inevitable roadblocks, he said, “These studies in animals basically reveal that the door is not completely shut for this patient population. There are going to be strategies that can be developed to help them. The brain is not lacked down. You can ply it with pharmaceutical reagents, and they can reanimate and restore functionality.”
Dr. Garner said he expected that norepinephrine will be found to operate through a different, and perhaps complementary, pathway than does GABA-A. “The norepinephrine drug class is really about arousal, which is fundamentally different from the way the GABA drugs appear to work on neuronal circuits. Clearly a systematic approach comparing each will be invaluable to understanding mechanism and assessing their clinical importance.”
“We really are pushing this research to the human clinical side rapidly,” said Roger Reeves, PhD, who studies the disorder as a professor in the department of physiology of the Institute for Genetic Medicine at Johns Hopkins University School of Medicine. “If the mouse models translate directly to humans, we may have a positive affect on cognitive impact in adults who have Down syndrome. That's something that five years ago virtually no one in the Down syndrome community thought could happen. The implications are huge.”
Although drugs already on the market raise norepinephrine levels in the brain, such as venlafaxine (Effexor), researchers were adamant in advising clinicians against trying them in DS patients.
“To my thinking that's human experimentation,” said Dr. Reeves. “To tell a family who has a child with Down syndrome that they can benefit from a drug before clinical trials prove it scientifically — that's potentially dangerous.”
For all the progress, Dr. Garner and others lamented that little money is available for such research, either from NIH or nonprofit groups.
“There is no money to do any of this,” Dr. Garner said. “This is why the research is going so slowly.”
• Salehi A, Faizi M, Colas D, et al. Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med 2009. E-pub 2009 Nov. 18.
• Wiseman FK. Cognitive enhancement therapy for a model of Down syndrome. Sci Transl Med 2009; E-pub Nov. 18.
• Costa AC, Scott-McKean JJ, Stasko MR. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology 2008;33(7):1624–1632. E-pub 2007 Aug 15.
• Fernandez F, Morishita W, Zuniga E. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci 2007;10(4):411–413. E-pub 2007 Feb 25.