Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice - PubMed (original) (raw)

. 2010 Dec 17:1366:162-71.

doi: 10.1016/j.brainres.2010.09.107. Epub 2010 Oct 26.

Chunhong Liu, Pavel Belichenko, Steven J Clapcote, Shaomin Li, Annie Pao, Alexander Kleschevnikov, Allison R Bechard, Suhail Asrar, Rongqing Chen, Ni Fan, Zhenyu Zhou, Zhengping Jia, Chu Chen, John C Roder, Bin Liu, Antonio Baldini, William C Mobley, Y Eugene Yu

Affiliations

Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice

Tao Yu et al. Brain Res. 2010.

Abstract

As the genomic basis for Down syndrome (DS), human trisomy 21 is the most common genetic cause of intellectual disability in children and young people. The genomic regions on human chromosome 21 (Hsa21) are syntenic to three regions in the mouse genome, located on mouse chromosome 10 (Mmu10), Mmu16, and Mmu17. Recently, we have developed three new mouse models using chromosome engineering carrying the genotypes of Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+, which harbor a duplication spanning the entire Hsa21 syntenic region on Mmu10, Mmu16, or Mmu17, respectively. In this study, we analyzed the hippocampal long-term potentiation (LTP) and cognitive behaviors of these models. Our results show that, while the genotype of Dp(17)1Yey/+ results in abnormal hippocampal LTP, the genotype of Dp(16)1Yey/+ leads to both abnormal hippocampal LTP and impaired learning/memory. Therefore, these mutant mice can serve as powerful tools for further understanding the mechanism underlying cognitively relevant phenotypes associated with DS, particularly the impacts of different syntenic regions on these phenotypes.

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Figures

Figure 1

Figure 1

The duplicated regions in Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+ mice. The endpoints of the duplicated regions (i.e., the endpoints of the Hsa21 syntenic regions) are shown. Mrpl39 is the proximal endpoint for the Hsa21 trisomic segment in Ts65Dn mice. Abcg1 and U2af1 are the proximal and distal endpoints of the duplication in Ts1Yah mice, respectively. The evidence has shown that the triplications of Olig2, Olig1, Rcan1, Dyrk1a and/or Kcnj6 may contribute to the cognitively relevant mutant phenotypes, which are marked with ** (Ahn et al., 2006; Arron et al., 2006; Chakrabarti et al., 2010; Chung et al., 2009; Mark and Herlitze, 2000; Yamada et al., 1998).

Figure 2

Figure 2

Analysis of the mutant mice using Morris water maze tests. (A-D) Dp(10)1Yey/+ mice; (E-H) Dp(16)1Yey/+ mice; (I-L) Dp(17)1Yey/+ mice. The numbers of mutant mice and wild-type littermates used in the experiments were described in Materials and Methods. (A, E, I) Path-length to locate the platform (m, meter); (B, F, J) Latency to locate the platform (s, second); (C, G, K) Swimming speed during the learning trials (m/s, meter/second); (D, H, L) The relative amount of time spent in different quadrants in the probe test on the day after the end of the training trials. Based on ANOVA, there was no statistically significant genotype-block interaction in these tests.

Figure 2

Figure 2

Analysis of the mutant mice using Morris water maze tests. (A-D) Dp(10)1Yey/+ mice; (E-H) Dp(16)1Yey/+ mice; (I-L) Dp(17)1Yey/+ mice. The numbers of mutant mice and wild-type littermates used in the experiments were described in Materials and Methods. (A, E, I) Path-length to locate the platform (m, meter); (B, F, J) Latency to locate the platform (s, second); (C, G, K) Swimming speed during the learning trials (m/s, meter/second); (D, H, L) The relative amount of time spent in different quadrants in the probe test on the day after the end of the training trials. Based on ANOVA, there was no statistically significant genotype-block interaction in these tests.

Figure 3

Figure 3

Analysis of the mutant mice using contextual fear conditioning test. The numbers of mutant mice and wild-type littermates examined in the contextual fear conditioning tests were described in Materials and Methods. The percentages of time spent freezing before the foot-shock (baseline) as well as during the 24- and 72-hr contextual exposures are shown as a measure of contextual learning. (A) Dp(10)1Yey/+ mice; (B) Dp(16)1Yey/+ mice; (C) Dp(17)1Yey/+ mice.

Figure 4

Figure 4

Analysis of Dp(16)1Yey/+ mice's sensitivity to the electric foot-shock. The minimal levels of currents (mA) needed to elicit a response, either flinching or vocalizing, from the mutant mice (n=15) and the wild-type littermates (n=14) are shown.

Figure 5

Figure 5

Analysis of the mutant mice's hippocampal LTP. The electrophysiological recordings were carried out using hippocampal slices and the fEPSPs were induced by TBS. Recordings were carried out before and after the TBS inductions for the mutant mice and the wild-type littermates. Evoked potentials were normalized to the fEPSP recorded prior to TBS induction (baseline=100%). The data is presented as the percentage of fEPSP as a function of time. (A) Dp(10)1Yey/+ mice; (B) Dp(16)1Yey/+ mice; (C) Dp(17)1Yey/+ mice.

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