Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice

Abstract

We hypothesize that the trisomy 21 (Down syndrome) is the additive and interactive outcome of the triple copy of different regions of HSA21. Because of the small number of patients with partial trisomy 21, we addressed the question in the Mouse in which three chromosomal regions located on MMU10, MMU17 and MMU16 carries almost all the HSA21 homologs. Male mice from four segmental trisomic strains covering the D21S17-ETS2 (syntenic to MMU16) were examined with an exhaustive battery of cognitive tests, motor tasks and MRI and compared with TS65Dn that encompasses D21S17-ETS2. None of the four strains gather all the impairments (measured by the effect size) of TS65Dn strain. The 152F7 strain was close to TS65Dn for motor behavior and reference memory and the three other strains 230E8, 141G6 and 285E6 for working memory. Episodic memory was impaired only in strain 285E6. The hippocampus and cerebellum reduced sizes that were seen in all the strains indicate that trisomy 21 is not only a hippocampus syndrome but that it results from abnormal interactions between the two structures.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Allin M, Matsumoto H, Santhouse AM, Nosarti C, AlAsady MH, Stewart AL, Rifkin L, Murray RM (2001) Cognitive and motor function and the size of the cerebellum in adolescents born very pre-term. Brain 124:60–66

    Article  PubMed  Google Scholar 

  2. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S (2004) Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet 5:725–738

    Article  PubMed  Google Scholar 

  3. Arenas M.C., Daza-Losada M., Vidal-Infer A., Aguilar M.A., Minarro J., Rodriguez-Arias M. (2014). Capacity of novelty-induced locomotor activity and the hole-board test to predict sensitivity to the conditioned rewarding effects of cocaine. Physiol Behav 133, 152–160.

    Article  PubMed  Google Scholar 

  4. Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC (2009) The “Down syndrome critical region” is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J neurosci 29:5938–5948

    Article  PubMed  PubMed Central  Google Scholar 

  5. Blednov YA, Stoffel M, Alva H, Harris RA (2003) A pervasive mechanism for analgesia: activation of GIRK2 channels. Proc Natl Acad Sci USA 100:277–282

    Article  PubMed  Google Scholar 

  6. Boker LK, Blumstein T, Sadetzki S, Luxenburg O, Litvak I, Akstein E, Modan B (2001). Incidence of leukemia and other cancers in Down syndrome subjects in Israel. Int J Cancer 93, 741–744.

    Article  PubMed  Google Scholar 

  7. Bourgeois P, Roubertoux PL (2015) Finding endophenotypes for autism spectrum disorders (ASD): cDNA microarrays and brain transcripts. In: Neuromethods, Roubertoux PL (eds) Organism models of autism spectrum disorders. Springer, New York, pp 217–238

    Google Scholar 

  8. Breia P, Mendes R, Silvestre A, Goncalves MJ, Figueira MJ, Bispo R (2014) Adults with Down syndrome: characterization of a Portuguese sample. Acta Med Port 27:357–363

    Article  PubMed  Google Scholar 

  9. Carlier M, Roubertoux PL (2014) Genetic and environmental influences on intellectual disability in childhood. In: Finkel D. and Reynold C.A. (eds) Behavior genetics of cognition across the lifespan Springer, New york, pp 69–101

    Google Scholar 

  10. Carlier M, Desplanches AG, Philip N, Stefanini S, Vicari S, Volterra V, Deruelle C, Fisch G, Doyen AL, Swillen A (2011) Laterality preference and cognition: cross-syndrome comparison of patients with trisomy 21 (Down), del7q11.23 (Williams-Beuren) and del22q11.2 (DiGeorge or Velo-Cardio-Facial) syndromes. Behav Genet 41:413–422

    Article  PubMed  Google Scholar 

  11. Carr J (2012) Six weeks to 45 years: a longitudinal study of a population with Down syndrome. J Appl Res Intellect Disabil 25:414–422

    Article  PubMed  Google Scholar 

  12. Caston J, Chianale C, Mariani J (2004) Spatial memory of heterozygous staggerer (Rora(+)/Rora(sg)) versus normal (Rora(+)/Rora(+)) mice during aging. Behav Genet 34:319–324

    Article  PubMed  Google Scholar 

  13. Caubit X, Gubellini P, Andrieux J, Roubertoux PL, Metwaly M, Jacq B, Fatmi A, Had-Aissouni L, Kwan KY, Salin P et al. (2016). TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nat Genet

  14. Chabert C, Jamon M, Cherfouh A, Duquenne V, Smith DJ, Rubin E, Roubertoux PL (2004) Functional analysis of genes implicated in Down syndrome: 1. Cognitive abilities in mice transpolygenic for Down Syndrome Chromosomal Region-1 (DCR-1). Behav Genet 34:559–569

    Article  PubMed  Google Scholar 

  15. Chapman RS, Hesketh LJ (2001) Language, cognition, and short-term memory in individuals with Down syndrome. Down’s Syndr Res Pract 7:1–7

    Article  Google Scholar 

  16. Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Earlbaum Associates., Hillsdale, NJ

    Google Scholar 

  17. Colombel C, Lalonde R, Caston J (2004) The effects of unilateral removal of the cerebellar hemispheres on spatial learning and memory in rats. Brain Res 1004:108–115

    Article  PubMed  Google Scholar 

  18. Contarino A., Baca L., Kennelly A., Gold L.H. (2002). Automated assessment of conditioning parameters for context and cued fear in mice. Learning & memory 9, 89–96.

    Article  Google Scholar 

  19. Cooper A, Grigoryan G, Guy-David L, Tsoory MM, Chen A, Reuveny E (2012) Trisomy of the G protein-coupled K + channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice. Proc Natl Acad Sci USA 109:2642–2647

    Article  PubMed  PubMed Central  Google Scholar 

  20. Costanzo F, Varuzza C, Menghini D, Addona F, Gianesini T, Vicari S (2013) Executive functions in intellectual disabilities: a comparison between Williams syndrome and Down syndrome. Res Dev Disabil 34:1770–1780

    Article  PubMed  Google Scholar 

  21. Coussons-Read ME, Crnic LS (1996) Behavioral assessment of the Ts65Dn mouse, a model for Down syndrome: altered behavior in the elevated plus maze and open field. Behav Genet 26:7–13

    Article  PubMed  Google Scholar 

  22. Couzens D., Cuskelly M., Haynes M. (2011). Cognitive development and Down syndrome: age-related change on the Stanford-Binet test (fourth edition). Am J Intellect Dev Disabil 116: 181–204.

    Article  PubMed  Google Scholar 

  23. 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: 263–280.

    PubMed  Google Scholar 

  24. Delabar JM, Theophile D, Rahmani Z, Chettouh Z, Blouin JL, Prieur M, Noel B, Sinet PM (1993). Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur J Human Genet 1:114–124.

    Google Scholar 

  25. Denenberg VH (1969) Open-field bheavior in the rat: what does it mean? Ann N Y Acad Sci 159:852–859

    Article  PubMed  Google Scholar 

  26. Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 31:47–59

    Article  PubMed  Google Scholar 

  27. Escorihuela RM, Fernandez-Teruel A, Vallina IF, Baamonde C, Lumbreras MA, Dierssen M, Tobena A, Florez J (1995). A behavioral assessment of Ts65Dn mice: a putative Down syndrome model. Neurosci Lett 199:143–146

    Article  PubMed  Google Scholar 

  28. Escorihuela RM, Vallina IF, Martinez-Cue C, Baamonde C, Dierssen M, Tobena A, Florez J, Fernandez-Teruel A (1998). Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome. Neurosci Lett 247:171–174

    Article  PubMed  Google Scholar 

  29. Field A (2005) Discovering statistics using SPSS. SAGE, London

    Google Scholar 

  30. Galli M, Cimolin V, Ferrario D, Patti P, Heaney G, Freedland R, Albertini G, Brown WT (2013). Quantitative 3D evaluation of step ascent and descent in individuals with Down syndrome–analysis of a daily challenging task. J Intellect Disabil Res 57:1143–1151

    PubMed  Google Scholar 

  31. Ginsburg BE A, WC (1942) Some effects on conditioning on social dominance and subordination in inbred strains of mice. Physiol Zool 15:485–506

    Article  Google Scholar 

  32. Goddyn H, Leo S, Meert T, D’Hooge R (2006) Differences in behavioural test battery performance between mice with hippocampal and cerebellar lesions. Behav Brain Res 173:138–147

    Article  PubMed  Google Scholar 

  33. Grieco J, Pulsifer M, Seligsohn K, Skotko B, Schwartz A (2015). Down syndrome: Cognitive and behavioral functioning across the lifespan. Am J Med Genet Part C 169:135–149.

    Article  PubMed  Google Scholar 

  34. Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK et al (2000) The DNA sequence of human chromosome 21. Nature 405:311–319

    Article  PubMed  Google Scholar 

  35. Higurashi M, Oda M, Iijima K, Iijima S, Takeshita T, Watanabe N, Yoneyama K (1990) Livebirth prevalence and follow-up of malformation syndromes in 27,472 newborns. Brain development 12:770–773

    Article  PubMed  Google Scholar 

  36. Hodges H (1996). Maze procedures: the radial-arm and water maze compared. Brain Res Cognit Brain Res 3:167–181.

    Article  Google Scholar 

  37. Irie F, Badie-Mahdavi H, Yamaguchi Y (2012) Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. Proc Natl Acad Sci USA 109:5052–5056

    Article  PubMed  PubMed Central  Google Scholar 

  38. Jackson JF, North ER, 3rd, Thomas JG (1976). Clinical diagnosis of Down’s syndrome. Clin Genet 9:483–487.

    Article  PubMed  Google Scholar 

  39. Janzen LA, David D, Walker D, Hitzler J, Zupanec S, Jones H, Spiegler BJ (2015). Pre-Morbid developmental vulnerabilities in children with newly diagnosed acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 62:2183–2188.

    Article  PubMed  Google Scholar 

  40. Jiang X, Liu C, Yu T, Zhang L, Meng K, Xing Z, Belichenko PV, Kleschevnikov AM, Pao A, Peresie J, et al. (2015). Genetic dissection of the Down syndrome critical region. Human Mol Genet 24:6540–6551.

    Article  Google Scholar 

  41. Jover M, Ayoun C, Berton C, Carlier M (2010). Specific grasp characteristics of children with trisomy 21. Dev Psychobiol 52:782–793.

    Article  PubMed  Google Scholar 

  42. Kafkafi N, Lipkind D, Benjamini Y, Mayo CL, Elmer GI, Golani I (2003) SEE locomotor behavior test discriminates C57BL/6 J and DBA/2 J mouse inbred strains across laboratories and protocol conditions. Behav Neurosci 117:464–477

    Article  PubMed  Google Scholar 

  43. Kida E, Rabe A, Walus M, Albertini G, Golabek AA (2013). Long-term running alleviates some behavioral and molecular abnormalities in Down syndrome mouse model Ts65Dn. Exp Neurol 240:178–189.

    Article  PubMed  Google Scholar 

  44. Kleschevnikov AM, Belichenko PV, Gall J, George L, Nosheny R, Maloney MT, Salehi A, Mobley WC (2012). Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis 45:683–691.

    Article  PubMed  Google Scholar 

  45. Korenberg JR, Chen XN, Schipper R, Sun Z, Gonsky R, Gerwehr S, Carpenter N, Daumer C, Dignan P, Disteche C et al (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91:4997–5001

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lanfranchi S, Jerman O, Dal Pont E, Alberti A, Vianello R (2010). Executive function in adolescents with Down Syndrome. J Intellect Disabil Res 54:308–319.

    Article  PubMed  Google Scholar 

  47. Lavenex PB, Bostelmann M, Brandner C, Costanzo F, Fragniere E, Klencklen G, Lavenex P, Menghini D, Vicari S (2015). Allocentric spatial learning and memory deficits in Down syndrome. Front Psychol 6:62.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lipp HP, Wahlsten D (1992) Absence of corpus callosum. In: Driscoll P (ed) Genetically defined animal models of neurological disorders. Birkhauser, Boston, pp 152–174

    Google Scholar 

  49. Liu C, Belichenko PV, Zhang L, Fu D, Kleschevnikov AM, Baldini A, Antonarakis SE, Mobley WC, Yu YE (2011). Mouse models for Down syndrome-associated developmental cognitive disabilities. Dev Neurosci 33:404–413.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Lyle R, Bena F, Gagos S, Gehrig C, Lopez G, Schinzel A, Lespinasse J, Bottani A, Dahoun S, Taine L, et al. (2009). Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur J Human Genet 17:454–466.

    Article  Google Scholar 

  51. Lyon L, Saksida LM, Bussey TJ (2012) Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models. Psychopharmacology 220:647–672

    Article  PubMed  Google Scholar 

  52. Makanjuola RO, Hill G, Maben I, Dow RC, Ashcroft GW (1977) An automated method for studying exploratory and stereotyped behaviour in rats. Psychopharmacology 52:271–277

    Article  PubMed  Google Scholar 

  53. Matynia A, Kushner SA, Silva AJ (2002) Genetic approaches to molecular and cellular cognition: a focus on LTP and learning and memory. Annu Rev Genet 36:687–720

    Article  PubMed  Google Scholar 

  54. Maxson SC,Canastar A (2003). Conceptual and methodological issues in the genetics of mouse agonistic behavior. Horm Behav 44:258–262.

    Article  PubMed  Google Scholar 

  55. Menghini D, Costanzo F, Vicari S (2011) Relationship between brain and cognitive processes in Down syndrome. Behav Genet 41:381–393

    Article  PubMed  Google Scholar 

  56. Mezei G, Sudan M, Izraeli S, Kheifets L (2014). Epidemiology of childhood leukemia in the presence and absence of Down syndrome. Cancer Epidemiol 38:479–489.

    Article  PubMed  Google Scholar 

  57. Milner B, Squire LR, Kandel ER (1998) Cognitive neuroscience and the study of memory. Neuron 20:445–468

    Article  PubMed  Google Scholar 

  58. Nokia MS, Wikgren J (2010) Hippocampal theta activity is selectively associated with contingency detection but not discrimination in rabbit discrimination-reversal eyeblink conditioning. Hippocampus 20:457–460

    PubMed  Google Scholar 

  59. Olson LE, Richtsmeier JT, Leszl J, Reeves RH (2004) A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306:687–690

    Article  PubMed  PubMed Central  Google Scholar 

  60. Olson LE, Roper RJ, Sengstaken CL, Peterson EA, Aquino V, Galdzicki Z, Siarey R, Pletnikov M, Moran TH, Reeves RH (2007). Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice. Human Mol Genet 16:774–782.

    Article  Google Scholar 

  61. Palisano RJ, Walter SD, Russell DJ, Rosenbaum PL, Gemus M, Galuppi BE, Cunningham L (2001) Gross motor function of children with down syndrome: creation of motor growth curves. Arch Phys Med Rehabil 82:494–500

    Article  PubMed  Google Scholar 

  62. Palkovits M, Brownstein MJ (1988). Maps and guide to microdissection of the rat brain New York, Elsevier.

    Google Scholar 

  63. Patterson T, Rapsey CM, Glue P (2013). Systematic review of cognitive development across childhood in Down syndrome: implications for treatment interventions. J Intellect Disabil Res 57:306–318.

    Article  PubMed  Google Scholar 

  64. Paxinos G, Franklin KBJ (2004). The mouse brain in stereotaxic coordinates, Compact. 2nd edn. Elsevier Academic Press, Amsterdam

    Google Scholar 

  65. Peng GP, Feng Z, He FP, Chen ZQ, Liu XY, Liu P, Luo BY (2015). Correlation of hippocampal volume and cognitive performances in patients with either mild cognitive impairment or Alzheimer’s disease. CNS Neurosci Ther 21:15–22.

    Article  PubMed  Google Scholar 

  66. Pennington BF, Moon J, Edgin J, Stedron J, Nadel L (2003). The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev 74:75–93.

    Article  PubMed  Google Scholar 

  67. Pereira PL, Magnol L, Sahun I, Brault V, Duchon A, Prandini P, Gruart A, Bizot JC, Chadefaux-Vekemans B, Deutsch S, et al. (2009). A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome. Human Mol Genet 18:4756–4769.

    Article  Google Scholar 

  68. Poissonnier M, Saint-Paul B, Dutrillaux B, Chassaigne M, Gruyer P, de Blignieres-Strouk G (1976). [Partial trisomy 21 (21q21–21q22.2)]. Annales de genetique 19:69–73.

    PubMed  Google Scholar 

  69. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, Schmidt C, Bronson RT, Davisson MT (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet 11:177–184

    Article  PubMed  Google Scholar 

  70. Rigoldi C, Galli M, Condoluci C, Carducci F, Onorati P, Albertini G (2009) Gait analysis and cerebral volumes in Down’s syndrome. Funct Neurol 24:147–152

    PubMed  Google Scholar 

  71. Rosin JM, McAllister BB, Dyck RH, Percival CJ, Kurrasch DM, Cobb J (2015) Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination. Dev Biol 399:54–67

    Article  PubMed  Google Scholar 

  72. Roubertoux PL, Carlier M (2009) Neurogenetic analysis and cognitive functions in Trisomy 21. In: Kim Y.K.K. (ed) Handbook of behavior genetics. Springer, New York, pp 175–185

    Google Scholar 

  73. Roubertoux PL, Carlier M (2010). Mouse models of cognitive disabilities in trisomy 21 (Down syndrome). Am J Med Genet Part C 154 C:400–416.

    Article  Google Scholar 

  74. Roubertoux PL, Sluyter F, Carlier M, Marcet B, Maarouf-Veray F, Cherif C, Marican C, Arrechi P, Godin F, Jamon M et al (2003) Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet 35:65–69

    Article  PubMed  Google Scholar 

  75. Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, Epstein CJ, Huang TT (1998) Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc Natl Acad Sci USA 95:6256–6261

    Article  PubMed  PubMed Central  Google Scholar 

  76. Sago H, Carlson EJ, Smith DJ, Rubin EM, Crnic LS, Huang TT, Epstein CJ (2000). Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr Res 48:606–613.

    Article  PubMed  Google Scholar 

  77. Sanderson DJ, Bannerman DM (2011). Competitive short-term and long-term memory processes in spatial habituation. J Exp Psychol Anim Behav Process 37:189–199.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Seregaza Z, Roubertoux PL, Jamon M, Soumireu-Mourat B (2006) Mouse models of cognitive disorders in trisomy 21: a review. Behav Genet 36:387–404

    Article  PubMed  Google Scholar 

  79. Siraly E, Szabo A, Szita B, Kovacs V, Fodor Z, Marosi C, Salacz P, Hidasi Z, Maros V, Hanak P et al (2015) Monitoring the early signs of cognitive decline in elderly by computer games: an MRI study. PloS ONE 10:e0117918

    Article  PubMed  PubMed Central  Google Scholar 

  80. Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, Watabe AM, O’Dell TJ, Fung J, Weier HU, Cheng JF et al (1997) Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nat Genet 16:28–36

    Article  PubMed  Google Scholar 

  81. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al. (2015). STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–452.

    Article  PubMed  Google Scholar 

  82. Tsao R, Kindelberger C (2009). Variability of cognitive development in children with Down syndrome: relevance of good reasons for using the cluster procedure. Res Dev Disabil 30:426–432.

    Article  PubMed  Google Scholar 

  83. Upchurch M, Wehner JM (1988) Differences between inbred strains of mice in Morris water maze performance. Behav Genet 18:55–68

    Article  PubMed  Google Scholar 

  84. Uyanik M, Bumin G, Kayihan H (2003) Comparison of different therapy approaches in children with Down syndrome. Pediatr Int 45:68–73

    Article  PubMed  Google Scholar 

  85. Vicari S (2006) Motor development and neuropsychological patterns in persons with Down syndrome. Behav Genet 36:355–364

    Article  PubMed  Google Scholar 

  86. Vicari S, Carlesimo GA (2006). Short-term memory deficits are not uniform in Down and Williams syndromes. Neuropsychol Rev 16:87–94.

    Article  PubMed  Google Scholar 

  87. Vis JC, Duffels MG, Winter MM, Weijerman ME, Cobben JM, Huisman SA, Mulder BJ (2009). Down syndrome: a cardiovascular perspective. J Int Disabil Res 53:419–425.

    Article  Google Scholar 

  88. Volden PA, Wonder EL, Skor MN, Carmean CM, Patel FN, Ye H, Kocherginsky M, McClintock MK, Brady MJ, Conzen SD (2013). Chronic social isolation is associated with metabolic gene expression changes specific to mammary adipose tissue. Cancer Prev Res 6:634–645.

    Article  Google Scholar 

  89. Watanabe H, Fujiyama A, Hattori M, Taylor TD, Toyoda A, Kuroki Y, Noguchi H, BenKahla A, Lehrach H, Sudbrak R et al (2004) DNA sequence and comparative analysis of chimpanzee chromosome 22. Nature 429:382–388

    Article  PubMed  Google Scholar 

  90. Wehner, JM, Radcliffe, RA (2004). Cued and contextual fear conditioning in mice. Current protocols in neuroscience / editorial board, Jacqueline N Crawley [et al] Chap. 8, Unit 8 5 C.

  91. Wehner JM, Radcliffe RA, Rosmann ST, Christensen SC, Rasmussen DL, Fulker DW, Wiles M (1997) Quantitative trait locus analysis of contextual fear conditioning in mice. Nat Genet 17:331–334

    Article  PubMed  Google Scholar 

  92. Weiss C, Disterhoft JF (2011) Exploring prefrontal cortical memory mechanisms with eyeblink conditioning. Behav Neurosci 125:318–326

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wikgren J, Nokia MS, Penttonen M (2010) Hippocampo-cerebellar theta band phase synchrony in rabbits. Neuroscience 165:1538–1545

    Article  PubMed  Google Scholar 

  94. Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, Asrar S, Pao A, Chen R, Fan N, et al. (2010a). A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Human Mol Genet 19:2780–2791.

  95. Yu T, Liu C, Belichenko P, Clapcote SJ, Li S, Pao A, Kleschevnikov A, Bechard AR, Asrar S, Chen R et al (2010b) Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice. Brain Res 1366:162–171

  96. Zhang L, Meng K, Jiang X, Liu C, Pao A, Belichenko PV, Kleschevnikov AM, Josselyn S, Liang P, Ye P, et al. (2014). Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits. Human Mol Genet 23:578–589.

    Article  Google Scholar 

Download references

Acknowledgements

We thank INSERM U 910 “Génétique Médicale, Génomique Fonctionnelle”, CNRS UMR 7290 Psychologie cognitive, Fédération de Recherche 3C–Comportement Cerveau–Cognition, and Aix Marseille University, and also the Fondation Jérôme Lejeune. AFI-Aveyron provided invaluable assistance with computer software for the MWM analysis and the Cavalieri stereology method. We wish to express our gratitude to the European Mouse Mutant Archive (EMMA) for the generous gift of two strains of segmental trisomic mice. Maire-Laure Dessain (UPS 44 TAAM, CNRS) genotyped the mice. Our special thanks to the anonymous reviewers of the first version of the manuscript and to Doctor Henri Bléhaut for his scientific support.

Author contributions

Conceived and designed the experiments: P-L Roubertoux, M. Carlier, S. Tordjman. Behavioral assessment of the mice: P-L Roubertoux, A. Ghata, C. Bartoli, M. Carlier. MRI: N Baril. P. Cau, P-L. Roubertoux. Data analysis : P-L Roubertoux, M Carlier. Molecular analysis: J. di Christofaro, P Bourgeois, P-L Roubertoux. Mouse breeding: C. Scajola. Wrote the paper: P-L Roubertoux, M Carlier. All the authors reviewed the manuscript for intellectual content and approved submission.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Pierre L. Roubertoux.

Ethics declarations

Conflict of interest

Pierre L. Roubertoux, Nathalie Baril, Pierre Cau, Christophe Scajola, Adeline Ghata, Catherine Bartoli, Patrice Bourgeois, Julie di Christofaro, Sylvie Tordjman, Michèle Carlier declare that they have no conflict of interests.

Ethical approval

The protocols for the present study were approved by the Comité d’éthique pour l’expérimentation animale n°14, under the title “Rôle de la région D21517-ET52 (MMU 16) dans les dysfonctions cérébrales de souris modèles du syndrome de Down,” with PL Roubertoux as the main investigator (reference number 23- 23092012, dated October 11, 2012).

Additional information

Edited by Stephen Maxson.

An erratum to this article is available at http://dx.doi.org/10.1007/s10519-017-9845-3.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Roubertoux, P.L., Baril, N., Cau, P. et al. Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice. Behav Genet 47, 305–322 (2017). https://doi.org/10.1007/s10519-017-9835-5

Download citation

Keywords

  • Trisomy 21
  • D21S17-ETS2 region
  • MRI
  • Protein–protein interactions
  • Effect size
  • Cognition