[01] Mohammed Rachidi, Molecular Genetics of Human Diseases, French Polynesia; University Paris 7 Denis Diderot, Paris, France.

Background: Trisomy of human chromosome 21 is the most frequent genetic cause of mental retardation or intellectual disability and others phenotypes, including developmental defects, dysmorphic features and cognitive impairments collectively known as Down syndrome. Mainly a consequence of developmental and functional brain alterations, the mental retardation is the most invariable and invalidating neuropathological characteristic caused by the overdosage of genes triplicated in the chromosome 21. Methods and Results: The cytogenetic and molecular analysis facilitate the identification of the minimal region or Down Syndrome Chromosomal Region responsible for many phenotypes including mental retardation as the major constant phenotype caused by the overexpression of chromosome 21 genes. The complete sequence of human chromosome 21 and the transcriptome analysis in Down syndrome patients and in trisomic mouse models facilitate the genetic dissection of neurological and cognitive phenotypes. As a result of high degree of conservation of genomes and of molecular mechanisms between mouse and human, the mouse models of Down syndrome showed similar neuropathological features seen in Down syndrome persons and facilitate the identification of associated genetic targets. Conclusion: The genetic dissection of neurological phenotypes in trisomic mouse models highly developed our understanding of cellular and molecular mechanisms of gene overexpression caused by trisomy 21 and contributed significantly to the identification of specific genetic targets for pharmacological therapeutics. These pharmacological treatments in mouse models of Down syndrome allowed successfully post-drug rescue of neurological alterations and associated cognitive deficits and could be useful therapeutic tools of neurocognitive deficits and mental retardation seen in Down syndrome persons.

Down Syndrome and Trisomy 21, Mental Retardation, Trisomic Mouse Models, Neurological Phenotypes, Learning and Memory, Molecular Targets, Genetic Pathways, Pharmacotherapies.

[01] Lejeune, J. (1990). Pathogenesis of mental deficiency in trisomy 21. American Journal Med. Genetics, 7 (Suppl.): 20-30. [02] Stoll, C., Alembik, Y., Dott, B. and Roth, M. P. (1990). Epidemiology of Down syndrome in 118,265 consecutive births. American Journal Med. Genetics, 7 (Suppl.): 79-83. [03] Pulsifer, M. B. (1996). The neuropsychology of mental retardation. J. Int. Neuropsychol. Soc., 2: 159-176. [04] Ferencz, C., Neill, C. A., Boughman, J. A., Rubin, J. D., Brenner, J. I. and Perry, L. W. (1989). Congenital cardiovascular malformations associated with chromosome abnormalities: An epidemiologic study. Journal Pediatr., 114: 79-86. [05] Puffenberger, E. G., Kauffman, E. R., Bolk, S., Matise, T. C., Washington, S. S., Angrist, M., Weissenbach, J., Garver, K. L., Mascari, M. and Ladda, R. (1994). Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Human Mol. Genet., 3: 1217-1225. [06] Epstein, C. J. (1995). Down syndrome (trisomy 21). In: Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. (Eds.), The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Inc., New York, pp. 749–794. [07] Cohen, W. I. (1999). Health care guidelines for individuals with Down syndrome: 1999 revision. Down Synd. Quart., 4: 1-16. [08] Wisniewski, K. E. (1990). Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. American Journal Med. Genetics., 7: 274-281. [09] Raz, N., Torres, I. J., Briggs, S. D., Spencer, W. D., Thornton, A. E., Loken, W. J., Gunning, F. M., McQuain, J. D., Driesen, N. R. and Acker, J. D. (1995). Selective neuroanatomic abnormalities in Down’s syndrome and their cognitive correlates: evidence from MRI morphometry. Neurology, 45: 356-366. [10] Hodapp, R. M., Ewans, D. E. and Gray, F. L. (1999). Intellectual development in children with Down syndrome. In: Rondal, J. A., Perera, J., Nadel, L. (Eds.), Down Syndrome: A Review of Current Knowledge. Whurr Publisher, London, pp. 124-132. [11] Chapman, R. S. and Hesketh, L. J. (2000). Behavioral phenotype of individuals with Down syndrome. Mental Retardation Developmental Disabilities. Research. Rev., 6: 84-95. [12] Brown, J. H., Johnson, M. H., Patterson, S. J., Gilmore, R., Longhi, E., and Karmiloff-Smith, A. (2003). Spatial representation and attention in toddlers with Williams syndrome and Down syndrome. Neuropsychologia, 41: 1037-1046. [13] Rahmani, Z., Blouin, J. L., Creau-Goldberg, N., Watkins, P. C., Mattei, J. F., Poissonnier, M., Prieur, M., Chettouh, Z., Nicole, A., Aurias, A., Sinet, P. M. and Delabar, J. M. (1989). Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome. Proc. Natl. Acad. Sci., 86: 5958-5962. [14] Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., Noel, B. and Sinet, P. M. (1993). Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur. J. Human Genetics, 1: 114-124. [15] Hattori, M., Fujiyama, A., Taylor, T. D., Watanabe, H., Yada, T., Park, H. S., Toyoda, A., Ishii, K., Totoki,Y., Choi, D. K., Groner, Y., Soeda, E., Ohki, M., Takagi, T., Sakaki, Y., Taudien, S., Blechschmidt, K., Polley, A., Menzel, U., Delabar, J., Kumpf, K., Lehmann, R., Patterson, D., Reichwald, K., Rump, A., Schillhabel, M., Schudy, A., Zimmermann,W., Rosenthal, A., Kudoh, J., Schibuya, K., Kawasaki, K., Asakawa, S., Shintani, A., Sasaki, T., Nagamine, K., Mitsuyama, S., Antonarakis, S. E., Minoshima, S., Shimizu, N., Nordsiek, G., Hornischer, K., Brant, P., Scharfe, M., Schon, O., Desario, A., Reichelt, J., Kauer, G., Blocker, H., Ramser, J., Beck, A., Klages, S., Hennig, S., Riesselmann, L., Dagand, E., Haaf, T.,Wehrmeyer, S., Borzym, K., Gardiner, K., Nizetic, D., Francis, F., Lehrach, H., Reinhardt, R. and Yaspo, M. L., (2000). The DNA sequence of human chromosome 21. Nature, 405: 311-319. [16] International Human Genome Sequencing Consortium (2004). Finishing the euchromatic sequence of the human genome. Nature, 431: 931-945. [17] Mao, R., Zielke, C. L., Zielke, H. R. and Pevsner, J. (2003). Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics, 81: 457-467. [18] Lyle, R., Gehrig, C., Neergaard-Henrichsen, C., Deutsch, S. and Antonarakis, S. E. (2004). Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Res., 14: 1268-1274. [19] Deutsch, S., Lyle, R., Dermitzakis, E. T., Attar, H., Subrahmanyan, L., Gehrig, C., Parand, L., Gagnebin, M., Rougemont, J., Jongeneel, C. V. and Antonarakis, S. E. (2005). Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes. Human Molecular Genetics, 14: 3741-3749. [20] Sultan, M., Piccini, I., Balzereit, D., Herwig, R., Saran, N. G., Lehrach, H., Reeves, R. H. and Yaspo, M. L. (2007). Gene expression variation in Down's syndrome mice allows prioritization of candidate genes. Genome Biol., 8: R91. [21] Davisson, M. T., Schmidt, C. and Akeson, E C. (1990). Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog. Clin. Biol. Res., 360: 263-280. [22] Dierssen, M., Vallina, I. F., Baamonde, C., Garcia-Calatayud, S., Lumbreras, M. A. and Florez, J. (1997). Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome. Brain Res., 749: 238-244. [23] Insausti, A. M., Megias, M., Crespo, D., Cruz-Orive, L. M., Dierssen, M., Vallina, I. F., Insausti, R., Florez, J. and Vallina, T. F. (1998). Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of Down syndrome. Neuroscience Lett., 253: 175-178. [24] Siarey, R. J., Stoll, S. I., Rapoport, S. I. and Galdzicki, Z. (1997). Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome. Neuropharmacology, 36: 1549-1554. [25] Siarey, R. J., Carlson, E. J., Epstein, C. J., Balbo, A., Rapoport, S. I. and Galdzicki, Z. (1999). Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology, 38: 1917-1920. [26] Baxter, L. L., Moran, T. H., Richtsmeier, J. T., Troncoso, J. and Reeves, R. H. (2000). Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Human Mol. Genet., 9: 195-202. [27] Granholm, A. C., Sanders, L. A. and Crnic, L. S. (2000). Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down’s syndrome. Exp. Neurol., 161: 647-663. [28] Salehi, A., Delcroix, J. D., Belichenko, P. V., Zhan, K., Wu, C., Valletta, J. S., Takimoto-Kimura, R., Kleschevnikov, A. M., Sambamurti, K., Chung, P. P., Xia,W., Villar, A., Campbell, W. A., Kulnane, L. S., Nixon, R. A., Lamb, B. T., Epstein, C. J., Stokin, G. B., Goldstein, L. S. and Mobley, W. C. (2006). Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron, 51: 29-42. [29] Kurt, M. A., Davies, D. C., Kidd, M., Dierssen, M. and Florez, J. (2000). Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice. Brain Res., 858: 191-197. [30] Kurt, M. A., Kafa, I. M., Dierssen, M. and Davies, C. D. (2004). Deficits of neuronal density in CA1 and synaptic density in the dentatgyrus, CA3 and CA1, in a mouse model of Down syndrome. Brain Res., 1022: 101-109. [31] Belichenko, P. V., Masliah, E., Kleschevnikov, A. M., Villar, A. J., Epstein, C. J., Salehi, A. and Mobley, W. C. (2004). Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. J. Comp. Neurol., 480: 281-298. [32] Costa, A. C., Walsh, K. and Davisson, M. T. (1999). Motor dysfunction in a mouse model for Down syndrome. Physiol. Behav., 68: 211-220. [33] Martinez-Cue, C., Baamonde, C., Lumbreras, M. A., Vallina, I. F., Dierssen, M. and Florez, J. (1999). A murine model for Down syndrome shows reduced responsiveness to pain. Neuroreport, 10: 1119-1122. [34] Hyde, L. A., Frisone, D. F., Crnic, L. S., 2001. Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function. Behav. Brain Res. 118, 53-60. [35] Reeves, R. H., Irving, N. G., Moran, T. H., Wohn, A., Kitt, C., Sisodia, S. S., Schmidt, C., Bronson, R. T. and Davisson, M. T. (1995). A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genetics, 11: 177-184. [36] Demas, G. E., Nelson, R. J., Krueger, B. K. and Yarowsky, P. J. (1996). Spatial memory deficits in segmental trisomic Ts65Dn mice. Behav. Brain Res., 82: 85-92. [37] Demas, G. E., Nelson, R. J., Krueger, B. K. and Yarowsky, P. J. (1998). Impaired spatial working and reference memory in segmental trisomy (Ts65Dn) mice. Behav. Brain Res., 90: 199-201. [38] Sago, H., Carlson, E. J., Smith, D. J., Rubin, E. M., Crnic, L. S., Huang, T.-T. and Epstein, C. J. (2000). Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr. Res., 48: 606-613. [39] Bimonte-Nelson, H. A., Hunter, C. L., Nelson, M. E. and Granholm, A. C. (2003). Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome. Behav. Brain Res., 139: 47-57. [40] Rachidi, M. and Lopes, C. (2008). Mental retardation and associated neurological dysfunctions in Down syndrome: a consequence of dysregulation in critical chromosome 21 genes and associated molecular pathways. Eur. J. Paediatric Neurology, 12: 168-182. [41] Arron, J. R., Winslow, M. M., Polleri, A., Chang, C. P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A. and Crabtree, G. R., (2006). NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature, 441: 595-600. [42] Smith, D. J., Stevens, M. E., Sudanagunta, S. P., Bronson, R. T., Makhinson, M. Watabe, A. M., O’Dell, T. J., Fung, J.,Weier, H. U., Cheng, J. F. and Rubin, E. M. (1997). Functional screening of 2 Mb of human chromosome 21q22,2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nature Genetics, 16, 28-36. [43] Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., Oset, M., Gonzalez, J. R., Florez, J., Fillat, C. and Estivill, X. (2001). Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down’s syndrome. Human Molecular Genetics, 10: 1915-1923. [44] Ahn, K. J., Jeong, H. K., Choi, H. S., Ryoo, S. R., Kim, Y. J., Goo, J. S., Choi, S. Y. and Han, J. S. (2006). DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiology Diseases, 22: 463-472. [45] Ortiz-Abalia, J., Sahun, I., Altafaj, X., Andreu, N., Estivill, X., Dierssen, M. and Fillat, C., (2008). Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of Down syndrome. American Journal Human Genetics, 83: 479-488. [46] Guedj, F., Sébrié, C., Rivals, I., Ledru, A., Paly, E., Bizot, J. C., Smith, D., Rubin, E., Gillet, B., Arbones, M. and Delabar, J. M. (2009). Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PloS One, 4: e4606. [47] Fernandez, F., Morishita, W., Zuniga, E., Nguyen, J., Blank, M., Malenka, R. C. and Garner, C. C., (2007). Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nature Neuroscience, 10: 411-413. [48] Rueda, N., Florez J. and Martinez-Cué, C. (2008). Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome. Neuroscience Letters, 433: 22-27. [49] Costa, A. C. S., Scott-McKean, J. J., and Stasko M. R. (2008). Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a conditioning fear test. Neuropsychopharmacology, 33: 1624-1632. [50] Rueda, N., Llorens-Martín, M., Flórez, J., Valdizán, E., Banerjee, P. et al. (2010). Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome. J. Alzheimer Disease, 21(1): 277-290. [51] Bianchi, P., Ciani, E., Guidi, S., Trazzi, S., Felice, D., Grossi, G., Fernandez, M., Giuliani, A., Calzà, L. andBartesaghi R. (2010). Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome. Journal of Neuroscience, 30(26): 8769-8779. [52] Guidi, S., Stagni, F., Bianchi, P., Ciani, E., Giacomini, A., De Franceschi, M., Moldrich, R., Kurniawan, N., Mardon, K., Giuliani, A., Calza, L., and Bartesaghi, R. (2014). Prenatal pharmacotherapy rescues brain development in a Down’s syndrome mouse model. Brain, 137(Pt 2): 380-401. [53] Begenisic, T., Baroncelli, L., Sansevero, G., Milanese, M., Bonifacino, T., Bonanno, G., Cioni, G., Maffei, L. andSale, A. (2014). Fluoxetine in adulthood normalizes GABA release and rescues hippocampal synaptic plasticity and spatial memory in a mouse model of Down syndrome. Neurobiology Diseases, 63: 12-19.