JAX® Mice Strain May Hold Key to Treating Down Syndrome

JAX® NOTES Issue 508, Winter 2008

Down syndrome (DS) is the leading genetic cause of mental retardation, affecting about 1 in 800 live births. It results from a trisomy of all or most of Chromosome (Chr) 21. Symptoms include varying degrees of mental retardation, characteristic craniofacial features, Alzheimer-like pathology after the third or fourth decade of life, and, occasionally, problems such as childhood leukemia and gastro-intestinal disorders.

The most complete and widely accepted animal model of DS is JAX® Mice strain B6EiC3Sn a/A-Ts(1716)65Dn (001924, abbreviated Ts65Dn), a strain constructed almost 20 years ago by Muriel Davisson PhD, a Tremont, Maine native and Senior Staff Scientist at The Jackson Laboratory (Davisson et al. 1990, 1993; Reeves et al. 1995). Human Chr 21 genes are conserved in mouse Chrs 10, 16, and 17, with the majority on Chr 16. Ts65Dn mice have an extra chromosome carrying a third copy of nearly all those Chr 16 genes (Akeson et al. 2001; Gardiner et al. 2002, 2003). Although they do not present all the features associated with DS (e.g., no congenital heart defects or Alzheimer-type pathology), Ts65Dn mice display many DS phenotypes, including significant learning and memory deficits, craniofacial dysmorphology, and motor dysfunction.

Recently, researchers at the University of Colorado at Denver and Health Sciences Center (UCDHSC) reported using memantine, an FDA-approved drug used to treat Alzheimer's disease, to reverse DS-associated learning deficits in the Ts65Dn mouse, possibly paving the way for the development of a therapy to increase the learning capacity of people with DS (Costa et al. 2007).

To conduct the study, researchers placed Ts65Dn and control mice in a special chamber and exposed them to a brief and mild electric stimulus. When placed in the same chamber 24 hours later, control mice froze, remembering the unpleasant feeling associated with the stimulus, but Ts65Dn mice walked around the chamber as if they had never experienced an unpleasant feeling. However, when Ts65Dn mice were placed in the chamber and exposed to the unpleasant stimulus after having received only two doses of memantine (15 minutes before the first exposure and 15 minutes before the second exposure, 24 hours later), they froze just as the control mice did. The behavior of the two groups of mice was statistically indistinguishable. The most important memantine dose seemed to be the first one, suggesting that the drug improves memory formation rather than memory retrieval. In a press release about the study, the authors comment that this "is the first instance in which acute injection of a drug agent has improved the behavioral performance of Down syndrome mice in a test of learning and memory."

Alberto Costa MD PhD, associate professor of medicine and neuroscience at UCDHSC School of Medicine and lead author of the study, began his research career on Down syndrome as a Research Scientist in Dr. Davisson's research group at The Jackson Laboratory. He has a 12-year-old daughter with Down syndrome. He hopes to lead a team of physicians and psychologists in a pilot, placebo-controlled, double-blind clinical trial to translate the research results into a potential DS therapy. "After 11 years of working in the field of Down syndrome, I feel fortunate to finally be in a position of being able to use scientific research to try to help improve the quality of the life of people who share the same genetic disorder as my daughter."

References

(Authors in bold are Jackson Laboratory scientists)

Akeson EC, Lambert JP, Narayanswami S, Gardiner K, Bechtel LJ, Davisson MT. 2001. Ts65Dn - localization of the translocation breakpoint and trisomic gene content is a mouse model for Down syndrome. Cytogenet Cell Genet 93:270-6.

Costa AC, Scott-McKean JJ, Stasko MR. 2007. 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. Aug 15 (Epub ahead of print).

Davisson MT, Schmidt C, Akeson EC. 1990. Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog Clin Biol Res 360:263-80.

Davisson MT, Schmidt C, Reeves RM, Irving NG, Akeson EC, Harris BS, Bronson RT. 1993. Segmental trisomy as a model for Down syndrome and other aneuploid conditions. In: The phenotypic mapping of Down syndrome and other aneuploid conditions. Wiley-Liss, New York, pp. 117-33.

Gardiner K, Fortna A, Bechtel L, Davisson MT. 2003. Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene 318:137-47.

Gardiner K, Slavov D, Bechtel L, Davisson M. 2002. Annotation of human chromosome 21 for relevance to Down syndrome: gene structure and expression analysis. Genomics 79:833-43.

JAX® NOTES. 2005. Down syndrome model distribution expanded. JAX® NOTES 497:4-5.

Reeves RH, Irving NG, Moran T, Wohn A, Sisodia SS, Schmidt C, Bronson RT, Davisson MT. 1995. A mouse model for Down syndrome exhibits learning and behavior deficits. Nat Genet 11:177-84.