The "Down syndrome critical region" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome - PubMed (original) (raw)

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

Nadia P Belichenko et al. J Neurosci. 2009.

Abstract

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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Figures

Figure 1.

Figure 1.

Spontaneous locomotor activity test of control (2N) and Ts1Rhr mice. The activity is shown in five sequential blocks of 2 min each. a, Total activity. b, Average velocity. c, Activity time. d, Activity counts. e, Vertical time. Results are mean ± SEM. Number of mice examined: 2N = 15; Ts1Rhr = 23. *p < 0.05, significantly different from 2N mice. Amb., Ambulatory.

Figure 2.

Figure 2.

Novel open field activity test. a, Representative activity tracers for 2N and Ts1Rhr mice during 10 min. b, Quantitative analysis of novel open field activity test breaking by 2 min blocks. Blue arrows show significantly decreased values and red arrows, significantly increased values for Ts1Rhr versus 2N. Note that Ts1Rhr mice spend more time and distance on average in the periphery of the field than 2N mice.

Figure 3.

Figure 3.

Novel object recognition test. a, Exploration time for the first 10 min familiarization phase for two identical objects (samples) and for the 1 h delay second 3 min phase for novel (novel) and old (sample) objects presentation. b, Exploration time as for a with 24 h delay. c, Discrimination ratio for novel object recognition test with 1 and 24 h delays. Results are mean ± SEM. Number of mice examined: 2N = 15; Ts1Rhr = 23. *p < 0.05, significantly different from 2N mice.

Figure 4.

Figure 4.

Hippocampal-dependent learning and synaptic plasticity in 2N and Ts1Rhr mice. a, Continuous alternation task in T-maze reveals dysfunction of the hippocampal system in Ts1Rhr mice. Number of mice examined: 2N = 15; Ts1Rhr = 23. b, Induction of LTP was also deficient in Ts1Rhr fascia dentata. Time course of the averaged initial slope of the fEPSP. A series of three tetanizations (arrows) applied at 5 min intervals evoked stable LTP in 2N, but failed to induce LTP in the Ts1Rhr FD (open and filled circles, respectively). c, A single tetanization train (arrow) evoked stable LTP in both 2N and Ts1Rhr FD after suppressing inhibition with picrotoxin. The results are mean ± SEM. The number of mice/slices examined: 2N = 6/6; Ts1Rhr = 6/6. *p < 0.05, significantly different from 2N mice.

Figure 5.

Figure 5.

Spine morphology and analysis of the dendrites of granule cells of fascia dentata. a, Confocal images of Lucifer yellow-microinjected dendrites and their spines in 2N and Ts1Rhr mice. Note enlarged spines in Ts1Rhr mice (arrows) as well as a reduction in their number in fascia dentata. Scale bar, 5 μm. b–d, Quantitative analysis of the frequency distributions of spine densities (b), spine head areas (c), and spine neck lengths (d) in 2N (open bars) and Ts1Rhr (solid bars) mice. Number of mice examined: 2N = 3; Ts1Rhr = 3.

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