STANFORD, Calif.—A recent study published by researchers atStanford University School of Medicine and Lucile Packard Children's Hospitaldescribes how boosting norepinephrine (NE) signaling in the brains of micegenetically engineered to mimic Down syndrome may improve the cognitivedevelopment of individuals with the genetic disorder. According to theresearchers, the finding could introduce the possibility of developing drugsthat enhance NE signaling, giving the Down syndrome community hope for a way tohelp children with Down's collect and modulate information.
The study followed a British Medical Journal report which estimates that the number of woman inEngland and Wales who conceived babies with Down's rose 70 percent over thelast 20 years. People with Down's suffer from myriad maladies, but the mostlife-altering may be moderate to severe life-long learning deficits.
Now, researchers are describing a treatment that improveslearning and memory in the Ts65Dn mouse, a model of Down's. The study,"Restoration of a Norepinephrine-Modulated Conextual Memory in a Mouse Model ofDown Syndrome," was published Nov. 18 in the American Association for theAdvancement of Science journal Science TranslationalMedicine.
Like people with DS, Ts65Dn mice display defects in learningand memory, functions that require a brain region called the hippocampus andthe NE-producing neurons that feed it, which begin in the locus coeruleus (LC),a nucleus in the brainstem. Dr. Ahmad Salehi, a senior researcher at StanfordUniversity School of Medicine, and colleagues found that although the LC in aTs65Dn mouse suffers severe degeneration, the cells that are targets forLC-generated NE remain intact and respond to exogenously suppliedneurotransmitter in vitro.
The report notes that the most common cause of mentalretardation in people, Down's arises from a chromosomal abnormality calledtrisomy 21, in which a third copy of chromosome 21 is present in cells,yielding an extra dose of ~300 genes. Ts65Dn mice have an extra copy of a pieceof mouse chromosome 16, which carries genes similar to about one-third of thoseon human chromosome 21.
Salehi notes that cognition in people with Down's doesn'tfail in ever aspect; rather, it fails in a structure-dependent fashion. Peoplewith Down's struggle to use spatial and contextual information to form newmemories, a function that depends on the hippocampus part of the brain, hesays. As a result, they have trouble with learning to navigate complexenvironments, but they are much better at remembering information linked tocolors, sounds or other sensory cues because such sensory memories arecoordinated by a different brain structure, the amygdala.
"If a person with Down's goes to a shopping mall and alwaysenters the store from the same direction, they will always be able to findwhere they need to go," Salehi explains. "But if one day, they enter the mallfrom a different parking lot, the sensory information they have retained is notthere, and they can't find it because that pretty much resets the whole brain.We set out to understand and try to fix that."
Salehi and his colleagues looked at what could be causingthe problems in the hippocampus. Normally, as contextual or relational memoriesare formed, hippocampal neurons receive norepinephrine from neurons in anotherpart of the brain, the locus coeruleus. The researchers showed that, likehumans with Down syndrome, the mice in their experiments experienced earlydegeneration of the locus coeruleus.
When the locus coeruleus broke down in the study's mice, theanimals failed at simple cognitive tests that required them to be aware ofchanges in the milieu: For instance, the genetically engineered mice, whenplaced in the strange environment of an unknown cage, did not build nests. Thatcontrasts with normal mice, which typically build nests in such circumstances.
However, by giving norepinephrine precursors to the micewith the Down-syndrome-like condition, the researchers could fix the problem.Only a few hours after they got the drugs, which were converted tonorepinephrine in the brain, these mice were just as good at nest-building andrelated cognitive tests as normal mice. Direct examination of neurons in thehippocampus of the genetically altered mice showed that these cells respondedwell to norepinephrine.
"Despite advanced locus coeruleus degeneration, we were ableto reverse contextual learning failure by using a prodrug for norepinephrinecalled L-threo-3,4-dihydroxyphenylserine, or xamoterol, a b1-adrenergicreceptor partial agonist," Salehi explains.
The study also provides the first direct link between locuscoeruleus breakdown in Down syndrome and a specific gene. People with Downsyndrome 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 inwhich spatial orientation and memory formation go awry. Salehi and colleaguespreviously linked APP to the breakdown of neurons that make acetylcholine inthese mice.
"Moreover, an increased gene dosage of App, in the contextof Down syndrome, was necessary for locus coeruleus degeneration. Our findingsraise the possibility that restoring norepinephrine-mediated neurotransmissioncould reverse cognitive dysfunction in Down syndrome," he adds.
Salehi cautions that it remains unclear whether the LCfunctions in contextual learning in humans, but he points out that LCdegeneration is evident in a variety of neurological disorders, including DSand Alzheimer's disease (AD), and people with DS display
hippocampal dysfunction as well as serious impairments incontextual learning.
"It is noteworthy that the App gene, which encodes the mousehomolog of the human amyloid b precursor protein, exists in triplicate inTs65Dn mice. Fragments of this protein build up in the brains of early-onset ADpatients, forming plaques that eventually kill neurons. Salehi, et al., show that this extra measure of App is required fordestruction of the LC neurons in Ts65Dn mice. Together, these new findings fillsome of the knowledge gaps regarding the genesis of neurological defects in DSand point toward an already approved drug as a starting point for therapiesthat address these independence-robbing deficits," the report concludes.
Salehi's collaborators at Stanford included life scienceresearch assistants Mehrdad Faizi, Janice Valletta and R. Takimoto-Kimura;research associates Damien Colas and Alexander Kleschevnikov; Jessenia Laguna,visiting fellow; Mehrdad Shamloo, senior research scientist; and formerdirector of the Stanford Institute for Neuro-Innovation & TranslationalNeurosciences Dr. William Mobley, who is now at the University ofCalifornia-San Diego. Mobley had also been director of Packard Children'sCenter for Down Syndrome.
The research was funded by grants from the NationalInstitutes of Health, the Larry L. Hillblom Foundation, the Down SyndromeResearch and Treatment Foundation, the Thrasher Research Fund, Adler Foundationand the Alzheimer's Association. The team has filed a patent applicationrelated to the research.
