Research ArticleDown Syndrome

Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome

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Science Translational Medicine  18 Nov 2009:
Vol. 1, Issue 7, pp. 7ra17
DOI: 10.1126/scitranslmed.3000258

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Mutant Mice Take Stroll Down Memory Lane

Just last month, the British Medical Journal published data from a study of pregnant women in England and Wales that revealed a startling statistic: The number of women in these countries who conceived babies with Down syndrome (DS) rose 70% over the past 20 years. Possible reasons include more sophisticated screening techniques and the fact that folks are starting families at older ages. People with DS suffer from myriad maladies, but the most life-altering likely is that which interferes with one’s ability to make independent decisions about one’s life—moderate to severe life-long learning deficits. Now, Salehi et al. describe a treatment that improves learning and memory in the Ts65Dn mouse, a model of DS.

The most common cause of mental retardation in people, DS arises from a chromosomal abnormality called trisomy 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 piece of mouse chromosome 16, which carries genes similar to about one-third of those on human chromosome 21. Like people with DS, Ts65Dn mice display defects in learning and memory, functions that require a brain region called the hippocampus and the norepinephrine (NE)–producing neurons that feed it, which begin in the locus coeruleus (LC), a nucleus in the brainstem. Salehi et al. found that although the LC in a Ts65Dn mouse suffers severe degeneration, the cells that are targets for LC-generated NE remain intact and respond to exogenously supplied neurotransmitter in vitro. When the Ts65Dn mice were treated with l-threo-3,4-dihydroxyphenylserine, a NE precursor that crosses the blood-brain barrier, two types of so-called contextual learning—fear conditioning and nest building—were restored.

It remains unclear whether the LC functions in contextual learning in humans, but LC degeneration is evident in a variety of neurological disorders, including DS and Alzheimer’s disease (AD), and people with DS display hippocampal dysfunction as well as serious impairments in contextual learning. It is noteworthy that the App gene, which encodes the mouse homolog of the human amyloid β precursor protein, exists in triplicate in Ts65Dn mice. Fragments of this protein build up in the brains of early-onset AD patients, forming plaques that eventually kill neurons. Salehi et al. show that this extra measure of App is required for destruction of the LC neurons in Ts65Dn mice. Together, these new findings fill some of the knowledge gaps regarding the genesis of neurological defects in DS and point toward an already approved drug as a starting point for therapies that address these independence-robbing deficits.

Footnotes

  • Present address: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.

  • Present address: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.

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