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J Neurosci. 2009 May 6;29(18):5938-48. doi: 10.1523/JNEUROSCI.1547-09.2009.

The "Down syndrome critical region" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome.

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Department of Neurology and Neurological Sciences and the Center for Research and Treatment of Down Syndrome, Stanford University Medical Center, Stanford, California 94305-5489, USA.


Down syndrome (DS) can be modeled in mice segmentally trisomic for mouse chromosome 16. Ts65Dn and Ts1Cje mouse models have been used to study DS neurobiological phenotypes including changes in cognitive ability, induction of long-term potentiation (LTP) in the fascia dentata (FD), the density and size of dendritic spines, and the structure of synapses. To explore the genetic basis for these phenotypes, we examined Ts1Rhr mice that are trisomic for a small subset of the genes triplicated in Ts65Dn and Ts1Cje mice. The 33 trisomic genes in Ts1Rhr represent a "DS critical region" that was once predicted to be sufficient to produce most DS phenotypes. We discovered significant alterations in an open field test, a novel object recognition test and in a T-maze task. As in Ts65Dn and Ts1Cje mice, LTP in FD of Ts1Rhr could be induced only after blocking GABA(A)-dependent inhibitory neurotransmission. In addition, widespread enlargement of dendritic spines and decreased density of spines in FD were preserved in Ts1Rhr. Twenty of 48 phenotypes showed significant differences between Ts1Rhr and 2N controls. We conclude that important neurobiological phenotypes characteristic of DS are conserved in Ts1Rhr mice. The data support the view that biologically significant trisomic phenotypes occur because of dosage effects of genes in the Ts1Rhr trisomic segment and that increased dosage is sufficient to produce these changes. The stage is now set for studies to decipher the gene(s) that play a conspicuous role in creating these phenotypes.

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