Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits - PubMed (original) (raw)

. 2014 Feb 1;23(3):578-89.

doi: 10.1093/hmg/ddt446. Epub 2013 Sep 16.

Kai Meng, Xiaoling Jiang, Chunhong Liu, Annie Pao, Pavel V Belichenko, Alexander M Kleschevnikov, Sheena Josselyn, Ping Liang, Ping Ye, William C Mobley, Y Eugene Yu

Affiliations

Li Zhang et al. Hum Mol Genet. 2014.

Abstract

Trisomy 21 (Down syndrome, DS) is the most common genetic cause of developmental cognitive deficits, and the so-called Down syndrome critical region (DSCR) has been proposed as a major determinant of this phenotype. The regions on human chromosome 21 (Hsa21) are syntenically conserved on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. DSCR is conserved between the Cbr1 and Fam3b genes on Mmu16. Ts65Dn mice carry three copies of ∼100 Hsa21 gene orthologs on Mmu16 and exhibited impairments in the Morris water maze and hippocampal long-term potentiation (LTP). Converting the Cbr1-Fam3b region back to two copies in Ts65Dn mice rescued these phenotypes. In this study, we performed similar conversion of the Cbr1-Fam3b region in Dp(16)1Yey/+ mice that is triplicated for all ∼115 Hsa21 gene orthologs on Mmu16, which also resulted in the restoration of the wild-type phenotypes in the Morris water maze and hippocampal LTP. However, converting the Cbr1-Fam3b region back to two copies in a complete model, Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+, failed to yield the similar phenotypic restorations. But, surprisingly, converting both the Cbr1-Fam3b region and the Hsa21 orthologous region on Mmu17 back to two copies in the complete model did completely restore these phenotypes to the wild-type levels. Our results demonstrated that the Hsa21 orthologous region on Mmu17 is a major determinant of DS-related developmental cognitive deficits. Therefore, the inclusion of the three copies of this Hsa21 orthologous region in mouse models is necessary for unraveling the mechanism underlying DS-associated developmental cognitive deficits and for developing effective interventions for this clinical manifestation.

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Figures

Figure 1.

Figure 1.

The mouse models of DS carrying three copies in the different Hsa21 orthologous regions on Mmu16. (A) Schematic representation of Hsa21 and the triplicated Hsa21 syntenic regions in the mouse models. (B) Agilent microarray CGH profiles show the duplication [_Dp(16)1Yey_] and the deletion [_Ms1Rhr_] in the Hsa21 orthologous region on Mmu16. CGH profiles 1 and 2 were generated using the DNA samples isolated from mouse models 1 and 2, respectively (A). No genomic alterations were detected on Mmu10 and Mmu17. Plotted are log2-transformed hybridization ratios of the DNA from mutants versus wild-type mouse DNA. The endpoint genes of the Hsa21 orthologous regions and the Ms1Rhr region are shown.

Figure 2.

Figure 2.

Analysis of the contribution of the _Cbr1_-Fam3b region to the Mmu16-associated performance in the Morris water maze test by the mouse models of DS. The _Dp(16)1Yey/_+ (n = 11), Dp(16)1Yey/Ms1Rhr (n = 10) and the wild-type control mice (n = 11) were examined in the Morris water maze. (A) Latency to locate the platform (s). (B) Path-length to locate the platform (m). (C) Swimming speed (m/s). (D) The relative amount of time spent in different quadrants during the probe test 1 day after the end of the training trials.

Figure 3.

Figure 3.

Analysis of the contribution of the _Cbr1_-Fam3b region to the Mmu16-associated electrophysiological phenotype in the mouse models of DS. In vitro characterizations of hippocampal synaptic transmission and plasticity were carried out by utilizing electrophysiological recordings in the CA1 region of the hippocampus in the brain slices of the _Dp(16)1Yey/_+ mice (n = 12), Dp(16)1Yey/Ms1Rhr mice (n = 10) and the wild-type control mice (n = 10). (A) Input–output curves were generated by applying stimuli of increasing intensity and measuring the initial slopes of the fEPSPs. (B) Paired-pulse facilitation was measured by applying two closely spaced stimuli and was expressed as the ratio of synaptic responses (fEPSP2/fEPSP1) as a function of interstimulus interval. (C) For measuring hippocampal LTP, the fEPSPs were induced by TBS. Recordings were carried out before and after TBS inductions for the DS mouse models and the wild-type control mice. Evoked potentials were normalized to the fEPSP recorded prior to TBS induction (baseline = 100%). The data are presented as the percentage of fEPSP as a function of time.

Figure 4.

Figure 4.

The mouse models of DS carrying three copies in the different Hsa21 orthologous regions on Mmu10, Mmu16 and Mmu17. (A) Schematic representation of Hsa21 and the triplicated Hsa21 syntenic regions in the mouse models. (B) Agilent microarray CGH profiles show duplications [Dp(10)1Yey, Dp(16)1Yey and _Dp(17)1Yey_] and the deletion [_Ms1Rhr_] in the Hsa21 orthologous region on Mmu10, Mmu16 and Mmu17. CGH profiles 1, 2, 3, 4 and 5 were generated using the DNA samples isolated from mouse models 1, 2, 3, 4 and 5, respectively (A). Plotted are log2-transformed hybridization ratios of the DNA from mutants versus wild-type mouse DNA. The endpoint genes of the Hsa21 orthologous regions and the Ms1Rhr region are shown.

Figure 5.

Figure 5.

Analysis of the contributions of the _Cbr1_-Fam3b region and the Hsa21 orthologous region on Mmu17 to the performance in the Morris water maze test by the mouse models of DS. The Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ (n = 12), Dp(10)1Yey/+;Dp(16)1Yey/Ms1Rhr;Dp(17)1Yey/+ (n = 14), Dp(10)1Yey/+;Dp(16)1Yey/Ms1Rhr (n = 13), Dp(16)1Yey/Ms1Rhr;Dp(17)1Yey/+ (n = 14), Dp(10)1Yey/+;Dp(17)1Yey/+ (n = 13) and the wild-type control mice (n = 13) were examined in the Morris water maze. (A) Latency to locate the platform (s). (B) Path-length to locate the platform (m). (C) Swimming speed (m/s). (D) The relative amount of time spent in different quadrants during the probe test 1 day after the end of the training trials.

Figure 6.

Figure 6.

Analysis of the contributions of the _Cbr1_-Fam3b region and the Hsa21 orthologous region on Mmu17 to the electrophysiological phenotype in the mouse models of DS. In vitro characterizations of hippocampal synaptic transmission and plasticity were carried out by utilizing electrophysiological recordings in the CA1 region of the hippocampus in the brain slices of the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ (n = 12), Dp(10)1Yey/+;Dp(16)1Yey/Ms1Rhr;Dp(17)1Yey/+ (n = 11), Dp(10)1Yey/+;Dp(16)1Yey/Ms1Rhr (n = 10), Dp(16)1Yey/Ms1Rhr;Dp(17)1Yey/+ (n = 10), Dp(10)1Yey/+;Dp(17)1Yey/+ (n = 10) and the wild-type control mice (n = 12). (A) Input–output curves were generated by applying stimuli of increasing intensity and measuring the initial slopes of the fEPSPs. (B) Paired-pulse facilitation was measured by applying two closely spaced stimuli and was expressed as the ratio of synaptic responses (fEPSP2/fEPSP1) as a function of the interstimulus interval. (C) For measuring hippocampal LTP, the fEPSPs were induced by TBS. Recordings were carried out before and after TBS inductions for the DS mouse models and the wild-type control mice. Evoked potentials were normalized to the fEPSP recorded prior to TBS induction (baseline = 100%). The data are presented as the percentage of fEPSP as a function of time.

References

    1. Pennington B.F., Moon J., Edgin J., Stedron J., Nadel L. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev. 2003;74:75–93. doi:10.1111/1467-8624.00522. -DOI -PubMed
    1. Pulsifer M.B. The neuropsychology of mental retardation. J. Int. Neuropsychol. Soc. 1996;2:159–176. doi:10.1017/S1355617700001016. -DOI -PubMed
    1. Chapman R.S., Hesketh L.J. Behavioral phenotype of individuals with Down syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 2000;6:84–95. doi:10.1002/1098-2779(2000)6:2<84::AID-MRDD2>3.0.CO;2-P. -DOI -PubMed
    1. Davisson M.T., Schmidt C., Akeson E.C. Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog. Clin. Biol. Res. 1990;360:263–280. -PubMed
    1. Reeves R.H., Irving N.G., Moran T.H., Wohn A., Kitt C., Sisodia S.S., Schmidt C., Bronson R.T., Davisson M.T. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat. Genet. 1995;11:177–184. doi:10.1038/ng1095-177. -DOI -PubMed

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