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Prospects for Improving Brain Function in Individuals with Down Syndrome

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Abstract

Down syndrome (DS), which results from an extra copy of chromosome 21 (trisomy 21), is the most common genetically defined cause of intellectual disability. Although no pharmacotherapy aimed at counteracting the cognitive and adaptive deficits associated with this genetic disorder has been approved at present, there have been several new promising studies on pharmacological agents capable of rescuing learning/memory deficits seen in mouse models of DS. Here, we will review the available mouse models for DS and provide a comprehensive, albeit not exhaustive review of the following preclinical research strategies: (1) SOD1 and antioxidant agents; (2) APP and γ-secretase inhibitors; (3) DYRK1A and the polyphenol epigallocatechin gallate (EGCG); (4) GIRK2 and fluoxetine; (5) adrenergic receptor agonists; (6) modulation of GABAA and GABAB receptors; (7) agonism of the hedgehog signaling pathway; (8) nerve growth factor (NGF) and other neurotrophic factors; (9) anticholinesterase (AChE) agents; and (10) antagonism of NMDA receptors. Finally, we will review briefly five different strategies in DS that have led to clinical studies that either have been concluded or are currently underway: (1) antioxidant therapy; (2) AChE therapy; (3) green tea extract therapy; (4) RG1662 therapy; and (5) memantine therapy. These are exciting times in DS research. Within a decade or so, it is well into the realm of possibility that new forms of pharmacotherapies might become valuable tools in the armamentarium of developmental clinicians, as adjutants to more traditional and proven forms of habilitative interventions aimed at improving the quality of life of individuals with DS.

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References

  1. Lejeune J, Turpin R, Gautier M. Le mongolism: premier exemple d’aberration autosomique humaine. Ann Genet. 1959;1(4):1–49.

    Google Scholar 

  2. Patterson D, Costa AC. Down syndrome and genetics—a case of linked histories. Nat Rev Genet. 2005;6(2):137–47.

    CAS  PubMed  Google Scholar 

  3. Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, et al. National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res A Clin Mol Teratol. 2006;76(11):747–56.

    CAS  PubMed  Google Scholar 

  4. CDC. Improved national prevalence estimates for 18 selected major birth defects—United States, 1999–2001. MMWR Morb Mortal Wkly Rep. 2006;54(51):1301–5.

  5. Roizen NJ, Patterson D. Down’s syndrome. Lancet. 2003;361(9365):1281–9.

    PubMed  Google Scholar 

  6. Turner S, Alborz A. Academic attainments of children with Down’s syndrome: a longitudinal study. Br J Educ Psychol. 2003;73(Pt 4):563–83.

    PubMed  Google Scholar 

  7. Abbeduto L, Warren SF, Conners FA. Language development in Down syndrome: from the prelinguistic period to the acquisition of literacy. Ment Retard Dev Disabil Res Rev. 2007;13(3):247–61.

    PubMed  Google Scholar 

  8. Chapman RS. Language learning in Down syndrome: the speech and language profile compared to adolescents with cognitive impairment of unknown origin. Downs Syndr Res Pract. 2006;10(2):61–6.

    PubMed  Google Scholar 

  9. Chapman RS, Hesketh LJ. Behavioral phenotype of individuals with Down syndrome. Ment Retard Dev Disabil Res Rev. 2000;6(2):84–95.

    CAS  PubMed  Google Scholar 

  10. Pennington BF, Moon J, Edgin J, Stedron J, Nadel L. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev. 2003;74(1):75–93.

    PubMed  Google Scholar 

  11. Leverenz JB, Raskind MA. Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol. 1998;150(2):296–304.

    CAS  PubMed  Google Scholar 

  12. Zigman W, Schupf N, Haveman M, Silverman W. The epidemiology of Alzheimer disease in intellectual disability: results and recommendations from an international conference. J Intellect Disabil Res. 1997;41(Pt 1):76–80.

    PubMed  Google Scholar 

  13. Carter G, Jancar J. Mortality in the mentally handicapped: a 50 year survey at the Stoke Park group of hospitals (1930–1980). J Ment Defic Res. 1983;27(Pt 2):143–56.

    PubMed  Google Scholar 

  14. Puri BK, Lekh SK, Langa A, Zaman R, Singh I. Mortality in a hospitalized mentally handicapped population: a 10-year survey. J Intellect Disabil Res. 1995;39(Pt 5):442–6.

    PubMed  Google Scholar 

  15. Morris JK, Alberman E, Mutton D, Jacobs P. Cytogenetic and epidemiological findings in Down syndrome: England and Wales 1989–2009. Am J Med Genet A. 2012;158A(5):1151–7.

    PubMed  Google Scholar 

  16. Epstein CJ. The conceptual bases for the phenotypic mapping of conditions resulting from aneuploidy. Prog Clin Biol Res. 1993;384:1–18.

    CAS  PubMed  Google Scholar 

  17. Shapiro BL. Down syndrome—a disruption of homeostasis. Am J Med Genet. 1983;14(2):241–69.

    CAS  PubMed  Google Scholar 

  18. Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, et al. The DNA sequence of human chromosome 21. Nature. 2000;405(6784):311–9.

    CAS  PubMed  Google Scholar 

  19. Sturgeon X, Gardiner KJ. Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions. Mamm Genome. 2008;22(5–6):261–71.

    Google Scholar 

  20. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36(Database issue):D154–8.

    Google Scholar 

  21. Kuhn DE, Nuovo GJ, Martin MM, Malana GE, Pleister AP, Jiang J, et al. Human chromosome 21-derived miRNAs are overexpressed in Down syndrome brains and hearts. Biochem Biophys Res Commun. 2008;370(3):473–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Keck-Wherley J, Grover D, Bhattacharyya S, Xu X, Holman D, Lombardini ED, et al. Abnormal microRNA expression in Ts65Dn hippocampus and whole blood: contributions to Down syndrome phenotypes. Dev Neurosci. 2011;33(5):451–67.

    CAS  PubMed  Google Scholar 

  23. Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, et al. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420(6915):520–62.

    CAS  PubMed  Google Scholar 

  24. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Med. 2010;7(3):e1000245.

    PubMed Central  PubMed  Google Scholar 

  25. Gardiner K. Predicting pathway perturbations in Down syndrome. J Neural Transm Suppl. 2003;67:21–37.

    CAS  PubMed  Google Scholar 

  26. Sommer CA, Henrique-Silva F. Trisomy 21 and Down syndrome: a short review. Braz J Biol. 2008;68(2):447–52.

    CAS  PubMed  Google Scholar 

  27. Cox DR, Smith SA, Epstein LB, Epstein CJ. Mouse trisomy 16 as an animal model of human trisomy 21 (Down syndrome): production of viable trisomy 16 diploid mouse chimeras. Dev Biol. 1984;101(2):416–24.

    CAS  PubMed  Google Scholar 

  28. Gropp A, Kolbus U, Giers D. Systematic approach to the study of trisomy in the mouse, II. Cytogenet Cell Genet. 1975;14(1):42–62.

    CAS  PubMed  Google Scholar 

  29. Davisson MT, Costa ACS. Mouse models of Down syndrome. In: Popko B, editor. Advances in neurochemisty. New York: Kluwer Academic/Plenum Publishers; 1999. p. 297–327.

    Google Scholar 

  30. Davisson MT, Schmidt C, Akeson EC. Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog Clin Biol Res. 1990;360:263–80.

    CAS  PubMed  Google Scholar 

  31. Davisson MT, Schmidt C, Reeves RH, Irving NG, Akeson EC, Harris BS, et al. Segmental trisomy as a mouse model for Down syndrome. Prog Clin Biol Res. 1993;384:117–33.

    CAS  PubMed  Google Scholar 

  32. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995;11(2):177–84.

    CAS  PubMed  Google Scholar 

  33. Akeson EC, Lambert JP, Narayanswami S, Gardiner K, Bechtel LJ, Davisson MT. Ts65Dn—localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome. Cytogenet Cell Genet. 2001;93(3–4):270–6.

    CAS  PubMed  Google Scholar 

  34. Gardiner K, Slavov D, Bechtel L, Davisson M. Annotation of human chromosome 21 for relevance to Down syndrome: gene structure and expression analysis. Genomics. 2002;79(6):833–43.

    CAS  PubMed  Google Scholar 

  35. Duchon A, Raveau M, Chevalier C, Nalesso V, Sharp AJ, Herault Y. Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome. Mamm Genome. 2011;22(11–12):674–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Baxter LL, Moran TH, Richtsmeier JT, Troncoso J, Reeves RH. Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum Mol Genet. 2000;9(2):195–202.

    CAS  PubMed  Google Scholar 

  37. Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, et al. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc Natl Acad Sci USA. 1998;95(11):6256–61.

    CAS  PubMed  Google Scholar 

  38. Siddiqui A, Lacroix T, Stasko MR, Scott-McKean JJ, Costa AC, Gardiner KJ. Molecular responses of the Ts65Dn and Ts1Cje mouse models of Down syndrome to MK-801. Genes Brain Behav. 2008;7(7):810–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Siarey RJ, Villar AJ, Epstein CJ, Galdzicki Z. Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome. Neuropharmacology. 2005;49(1):122–8.

    CAS  PubMed  Google Scholar 

  40. O’Doherty A, Ruf S, Mulligan C, Hildreth V, Errington ML, Cooke S, et al. An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science. 2005;309(5743):2033–7.

    PubMed Central  PubMed  Google Scholar 

  41. Olson LE, Richtsmeier JT, Leszl J, Reeves RH. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science. 2004;306(5696):687–90.

    CAS  PubMed  Google Scholar 

  42. Olson LE, Roper RJ, Sengstaken CL, Peterson EA, Aquino V, Galdzicki Z, et al. Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice. Hum Mol Genet. 2007;16(7):774–82.

    CAS  PubMed  Google Scholar 

  43. Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC. The “Down syndrome critical region” is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci. 2009;29(18):5938–48.

    CAS  PubMed  Google Scholar 

  44. Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, et al. A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Hum Mol Genet. 2010;19(14):2780–91.

    CAS  PubMed  Google Scholar 

  45. Costa AC, Scott-McKean JJ, Stasko MR. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology. 2008;33(7):1624–32.

    CAS  PubMed  Google Scholar 

  46. Costa AC, Stasko MR, Schmidt C, Davisson MT. Behavioral validation of the Ts65Dn mouse model for Down syndrome of a genetic background free of the retinal degeneration mutation Pde6b(rd1). Behav Brain Res. 2010;206(1):52–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Demas GE, Nelson RJ, Krueger BK, Yarowsky PJ. Spatial memory deficits in segmental trisomic Ts65Dn mice. Behav Brain Res. 1996;82(1):85–92.

    CAS  PubMed  Google Scholar 

  48. Demas GE, Nelson RJ, Krueger BK, Yarowsky PJ. Impaired spatial working and reference memory in segmental trisomy (Ts65Dn) mice. Behav Brain Res. 1998;90(2):199–201.

    CAS  PubMed  Google Scholar 

  49. Dowdy-Sanders NC, Wenger GR. Working memory in the Ts65Dn mouse, a model for Down syndrome. Behav Brain Res. 2006;168(2):349–52.

    CAS  PubMed  Google Scholar 

  50. Escorihuela RM, Vallina IF, Martinez-Cue C, Baamonde C, Dierssen M, Tobena A, et al. Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome. Neurosci Lett. 1998;247(2–3):171–4.

    CAS  PubMed  Google Scholar 

  51. Hampton TG, Stasko MR, Kale A, Amende I, Costa AC. Gait dynamics in trisomic mice: quantitative neurological traits of Down syndrome. Physiol Behav. 2004;82(2–3):381–9.

    CAS  PubMed  Google Scholar 

  52. Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci. 2007;10(4):411–3.

    CAS  PubMed  Google Scholar 

  53. Costa AC, Walsh K, Davisson MT. Motor dysfunction in a mouse model for Down syndrome. Physiol Behav. 1999;68(1–2):211–20.

    CAS  PubMed  Google Scholar 

  54. Parsons T, Ryan TM, Reeves RH, Richtsmeier JT. Microstructure of trabecular bone in a mouse model for Down syndrome. Anat Rec (Hoboken). 2007;290(4):414–21.

    Google Scholar 

  55. Hill CA, Reeves RH, Richtsmeier JT. Effects of aneuploidy on skull growth in a mouse model of Down syndrome. J Anat. 2007;210(4):394–405.

    PubMed  Google Scholar 

  56. Richtsmeier JT, Baxter LL, Reeves RH. Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice. Dev Dyn. 2000;217(2):137–45.

    CAS  PubMed  Google Scholar 

  57. Williams AD, Mjaatvedt CH, Moore CS. Characterization of the cardiac phenotype in neonatal Ts65Dn mice. Dev Dyn. 2008;237(2):426–35.

    PubMed  Google Scholar 

  58. Moore CS. Postnatal lethality and cardiac anomalies in the Ts65Dn Down syndrome mouse model. Mamm Genome. 2006;17(10):1005–12.

    CAS  PubMed  Google Scholar 

  59. Scott-McKean JJ, Chang B, Hurd RE, Nusinowitz S, Schmidt C, Davisson MT, et al. The mouse model of Down syndrome Ts65Dn presents visual deficits as assessed by pattern visual evoked potentials. Invest Ophthalmol Vis Sci. 2010;51(6):3300–8.

    PubMed  Google Scholar 

  60. Begenisic T, Spolidoro M, Braschi C, Baroncelli L, Milanese M, Pietra G, et al. Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down syndrome. Front Cell Neurosci. 2011;5:29.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25:103–26.

    CAS  PubMed  Google Scholar 

  62. Collingridge GL, Isaac JT, Wang YT. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci. 2004;5(12):952–62.

    CAS  PubMed  Google Scholar 

  63. Costa AC, Grybko MJ. Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome. Neurosci Lett. 2005;382(3):317–22.

    CAS  PubMed  Google Scholar 

  64. Kleschevnikov AM, Belichenko PV, Villar AJ, Epstein CJ, Malenka RC, Mobley WC. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J Neurosci. 2004;24(37):8153–60.

    CAS  PubMed  Google Scholar 

  65. Siarey RJ, Stoll J, Rapoport SI, Galdzicki Z. Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome. Neuropharmacology. 1997;36(11–12):1549–54.

    CAS  PubMed  Google Scholar 

  66. Siarey RJ, Carlson EJ, Epstein CJ, Balbo A, Rapoport SI, Galdzicki Z. Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology. 1999;38(12):1917–20.

    CAS  PubMed  Google Scholar 

  67. Scott-McKean JJ, Costa AC. Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine. Learn Mem. 2011;18(12):774–8.

    CAS  PubMed  Google Scholar 

  68. Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27(7):370–7.

    CAS  PubMed  Google Scholar 

  69. Strydom A, Dickinson MJ, Shende S, Pratico D, Walker Z. Oxidative stress and cognitive ability in adults with Down syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(1):76–80.

    CAS  PubMed  Google Scholar 

  70. Tan YH, Tischfield J, Ruddle FH. The linkage of genes for the human interferon-induced antiviral protein and indophenol oxidase-B traits to chromosome G-21. J Exp Med. 1973;137(2):317–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Groner Y, Elroy-Stein O, Avraham KB, Yarom R, Schickler M, Knobler H, et al. Down syndrome clinical symptoms are manifested in transfected cells and transgenic mice overexpressing the human Cu/Zn-superoxide dismutase gene. J Physiol (Paris). 1990;84(1):53–77.

    CAS  Google Scholar 

  72. Busciglio J, Yankner BA. Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature. 1995;378(6559):776–9.

    CAS  PubMed  Google Scholar 

  73. Borg J, London J. Copper/zinc superoxide dismutase overexpression promotes survival of cortical neurons exposed to neurotoxins in vitro. J Neurosci Res. 2002;70(2):180–9.

    CAS  PubMed  Google Scholar 

  74. Nikonenko AG, Radenovic L, Andjus PR, Skibo GG. Structural features of ischemic damage in the hippocampus. Anat Rec (Hoboken). 2009;292(12):1914–21.

    CAS  Google Scholar 

  75. Lockrow J, Prakasam A, Huang P, Bimonte-Nelson H, Sambamurti K, Granholm AC. Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model. Exp Neurol. 2009;216(2):278–89.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Shichiri M, Yoshida Y, Ishida N, Hagihara Y, Iwahashi H, Tamai H, et al. Alpha-tocopherol suppresses lipid peroxidation and behavioral and cognitive impairments in the Ts65Dn mouse model of Down syndrome. Free Radic Biol Med. 2011;50(12):1801–11.

    CAS  PubMed  Google Scholar 

  77. Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, et al. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987;235(4791):880–4.

    CAS  PubMed  Google Scholar 

  78. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science. 1987;235(4791):877–80.

    CAS  PubMed  Google Scholar 

  79. Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci USA. 1987;84(12):4190–4.

    CAS  PubMed  Google Scholar 

  80. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349(6311):704–6.

    CAS  PubMed  Google Scholar 

  81. Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, et al. APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain. 2006;129(Pt 11):2977–83.

    PubMed  Google Scholar 

  82. Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC. Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med. 2001;125(4):489–92.

    CAS  PubMed  Google Scholar 

  83. Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, et al. Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci USA. 1996;93(23):13333–8.

    CAS  PubMed  Google Scholar 

  84. Cooper JD, Salehi A, Delcroix JD, Howe CL, Belichenko PV, Chua-Couzens J, et al. Failed retrograde transport of NGF in a mouse model of Down’s syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc Natl Acad Sci USA. 2001;98(18):10439–44.

    CAS  PubMed  Google Scholar 

  85. Seo H, Isacson O. Abnormal APP cholinergic and cognitive function in Ts65Dn Down’s model mice. Exp Neurol. 2005;193(2):469–80.

    CAS  PubMed  Google Scholar 

  86. Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, et al. Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006;51(1):29–42.

    CAS  PubMed  Google Scholar 

  87. Netzer WJ, Powell C, Nong Y, Blundell J, Wong L, Duff K, et al. Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One. 2010;5(6):e10943.

    PubMed Central  PubMed  Google Scholar 

  88. Choi JH, Berger JD, Mazzella MJ, Morales-Corraliza J, Cataldo AM, Nixon RA, et al. Age-dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model. J Neurochem. 2009;110(6):1818–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature. 2006;441(7093):595–600.

    CAS  PubMed  Google Scholar 

  90. Chen-Hwang MC, Chen HR, Elzinga M, Hwang YW. Dynamin is a minibrain kinase/dual specificity Yak1-related kinase 1A substrate. J Biol Chem. 2002;277(20):17597–604.

    CAS  PubMed  Google Scholar 

  91. Yang EJ, Ahn YS, Chung KC. Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. J Biol Chem. 2001;276(43):39819–24.

    CAS  PubMed  Google Scholar 

  92. Guedj F, Sebrie C, Rivals I, Ledru A, Paly E, Bizot JC, et al. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS One. 2009;4(2):e4606.

    PubMed Central  PubMed  Google Scholar 

  93. Ahn KJ, Jeong HK, Choi HS, Ryoo SR, Kim YJ, Goo JS, et al. DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiol Dis. 2006;22(3):463–72.

    CAS  PubMed  Google Scholar 

  94. Park J, Song WJ, Chung KC. Function and regulation of Dyrk1A: towards understanding Down syndrome. Cell Mol Life Sci. 2009;66(20):3235–40.

    CAS  PubMed  Google Scholar 

  95. Bain J, McLauchlan H, Elliott M, Cohen P. The specificities of protein kinase inhibitors: an update. Biochem J. 2003;371(Pt 1):199–204.

    CAS  PubMed  Google Scholar 

  96. Noll C, Planque C, Ripoll C, Guedj F, Diez A, Ducros V, et al. DYRK1A, a novel determinant of the methionine-homocysteine cycle in different mouse models overexpressing this Down-syndrome-associated kinase. PLoS One. 2009;4(10):e7540.

    PubMed Central  PubMed  Google Scholar 

  97. Kobayashi T, Washiyama K, Ikeda K. Inhibition of G protein-activated inwardly rectifying K + channels by fluoxetine (Prozac). Br J Pharmacol. 2003;138(6):1119–28.

    CAS  PubMed  Google Scholar 

  98. Yamada M, Inanobe A, Kurachi Y. G protein regulation of potassium ion channels. Pharmacol Rev. 1998;50(4):723–60.

    CAS  PubMed  Google Scholar 

  99. Cramer NP, Best TK, Stoffel M, Siarey RJ, Galdzicki Z. GABAB–GIRK2-mediated signaling in Down syndrome. Adv Pharmacol. 2012;58:397–426.

    Google Scholar 

  100. Clark S, Schwalbe J, Stasko MR, Yarowsky PJ, Costa AC. Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome. Exp Neurol. 2006;200(1):256–61.

    CAS  PubMed  Google Scholar 

  101. Eisch AJ, Cameron HA, Encinas JM, Meltzer LA, Ming GL, Overstreet-Wadiche LS. Adult neurogenesis, mental health, and mental illness: hope or hype? J Neurosci. 2008;28(46):11785–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Virji-Babul N, Eichmann A, Kisly D, Down J, Haslam RH. Use of health care guidelines in patients with Down syndrome by family physicians across Canada. Paediatr Child Health. 2007;12(3):179–83.

    PubMed  Google Scholar 

  103. Myers BA, Pueschel SM. Major depression in a small group of adults with Down syndrome. Res Dev Disabil. 1995;16(4):285–99.

    CAS  PubMed  Google Scholar 

  104. Costa AC, Stasko MR, Stoffel M, Scott-McKean JJ. G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses. J Neurosci. 2005;25(34):7801–4.

    CAS  PubMed  Google Scholar 

  105. Stasko MR, Scott-McKean JJ, Costa AC. Hypothermic responses to 8-OH-DPAT in the Ts65Dn mouse model of Down syndrome. Neuroreport. 2006;17(8):837–41.

    CAS  PubMed  Google Scholar 

  106. Artigas F, Romero L, de Montigny C, Blier P. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci. 1996;19(9):378–83.

    CAS  PubMed  Google Scholar 

  107. Bianchi P, Ciani E, Guidi S, Trazzi S, Felice D, Grossi G, et al. Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome. J Neurosci. 2010;30(26):8769–79.

    CAS  PubMed  Google Scholar 

  108. Heinen M, Hettich MM, Ryan DP, Schnell S, Paesler K, Ehninger D. Adult-onset fluoxetine treatment does not improve behavioral impairments and may have adverse effects on the Ts65Dn mouse model of Down syndrome. Neural Plast. 2012;2012:467251.

    PubMed Central  PubMed  Google Scholar 

  109. Murchison CF, Zhang XY, Zhang WP, Ouyang M, Lee A, Thomas SA. A distinct role for norepinephrine in memory retrieval. Cell. 2004;117(1):131–43.

    CAS  PubMed  Google Scholar 

  110. Mann DM, Yates PO, Marcyniuk B, Ravindra CR. Pathological evidence for neurotransmitter deficits in Down’s syndrome of middle age. J Ment Defic Res. 1985;29(Pt 2):125–35.

    PubMed  Google Scholar 

  111. German DC, Manaye KF, White CL 3rd, Woodward DJ, McIntire DD, Smith WK, et al. Disease-specific patterns of locus coeruleus cell loss. Ann Neurol. 1992;32(5):667–76.

    CAS  PubMed  Google Scholar 

  112. Hoogendijk WJ, Pool CW, Troost D, van Zwieten E, Swaab DF. Image analyser-assisted morphometry of the locus coeruleus in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Brain. 1995;118(Pt 1):131–43.

    PubMed  Google Scholar 

  113. Zarow C, Lyness SA, Mortimer JA, Chui HC. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol. 2003;60(3):337–41.

    PubMed  Google Scholar 

  114. Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging. 2007;28(3):327–35.

    CAS  PubMed  Google Scholar 

  115. Dierssen M, Vallina IF, Baamonde C, Garcia-Calatayud S, Lumbreras MA, Florez J. Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome. Brain Res. 1997;749(2):238–44.

    CAS  PubMed  Google Scholar 

  116. Salehi A, Faizi M, Colas D, Valletta J, Laguna J, Takimoto-Kimura R, et al. Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med. 2009;1(7):7ra17.

    CAS  PubMed  Google Scholar 

  117. Tohgi H, Abe T, Takahashi S. The effects of l-threo-3,4-dihydroxyphenylserine on the total norepinephrine and dopamine concentrations in the cerebrospinal fluid and freezing gait in parkinsonian patients. J Neural Transm Park Dis Dement Sect. 1993;5(1):27–34.

    CAS  PubMed  Google Scholar 

  118. Faizi M, Bader PL, Tun C, Encarnacion A, Kleschevnikov A, Belichenko P, et al. Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down syndrome: activation of beta1-adrenergic receptor by xamoterol as a potential cognitive enhancer. Neurobiol Dis. 2011;43(2):397–413.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Best TK, Siarey RJ, Galdzicki Z. Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current. J Neurophysiol. 2007;97(1):892–900.

    CAS  PubMed  Google Scholar 

  120. Kleschevnikov AM, Belichenko PV, Gall J, George L, Nosheny R, Maloney MT, et al. Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2012;45(2):683–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Best TK, Cramer NP, Chakrabarti L, Haydar TF, Galdzicki Z. Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome. Exp Neurol. 2012;233(2):749–57.

    CAS  PubMed  Google Scholar 

  122. Coyle JT, Oster-Granite ML, Gearhart JD. The neurobiologic consequences of Down syndrome. Brain Res Bull. 1986;16(6):773–87.

    CAS  PubMed  Google Scholar 

  123. Pinter JD, Eliez S, Schmitt JE, Capone GT, Reiss AL. Neuroanatomy of Down’s syndrome: a high-resolution MRI study. Am J Psychiatry. 2001;158(10):1659–65.

    CAS  PubMed  Google Scholar 

  124. Aylward EH, Li Q, Honeycutt NA, Warren AC, Pulsifer MB, Barta PE, et al. MRI volumes of the hippocampus and amygdala in adults with Down’s syndrome with and without dementia. Am J Psychiatry. 1999;156(4):564–8.

    CAS  PubMed  Google Scholar 

  125. Rigoldi C, Galli M, Condoluci C, Carducci F, Onorati P, Albertini G. Gait analysis and cerebral volumes in Down’s syndrome. Funct Neurol. 2009;24(3):147–52.

    CAS  PubMed  Google Scholar 

  126. Roper RJ, Baxter LL, Saran NG, Klinedinst DK, Beachy PA, Reeves RH. Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice. Proc Natl Acad Sci USA. 2006;103(5):1452–6.

    CAS  PubMed  Google Scholar 

  127. Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron. 1999;22(1):103–14.

    CAS  PubMed  Google Scholar 

  128. Wallace VA. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol. 1999;9(8):445–8.

    CAS  PubMed  Google Scholar 

  129. Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A, McMahon AP. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol. 2004;270(2):393–410.

    CAS  PubMed  Google Scholar 

  130. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3(12):903–11.

    PubMed  Google Scholar 

  131. Trazzi S, Mitrugno VM, Valli E, Fuchs C, Rizzi S, Guidi S, et al. APP-dependent up-regulation of Ptch1 underlies proliferation impairment of neural precursors in Down syndrome. Hum Mol Genet. 2011;20(8):1560–73.

    CAS  PubMed  Google Scholar 

  132. Goodrich LV, Jung D, Higgins KM, Scott MP. Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube. Dev Biol. 1999;211(2):323–34.

    CAS  PubMed  Google Scholar 

  133. Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature. 2002;418(6900):892–7.

    CAS  PubMed  Google Scholar 

  134. Black IB. Trophic regulation of synaptic plasticity. J Neurobiol. 1999;41(1):108–18.

    CAS  PubMed  Google Scholar 

  135. Schinder AF, Poo M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 2000;23(12):639–45.

    CAS  PubMed  Google Scholar 

  136. Shooter EM. Early days of the nerve growth factor proteins. Annu Rev Neurosci. 2001;24:601–29.

    CAS  PubMed  Google Scholar 

  137. Yates CM, Simpson J, Gordon A, Maloney AF, Allison Y, Ritchie IM, et al. Catecholamines and cholinergic enzymes in pre-senile and senile Alzheimer-type dementia and Down’s syndrome. Brain Res. 1983;280(1):119–26.

    CAS  PubMed  Google Scholar 

  138. Holtzman DM, Li Y, Chen K, Gage FH, Epstein CJ, Mobley WC. Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration. Neurology. 1993;43(12):2668–73.

    CAS  PubMed  Google Scholar 

  139. Tuszynski MH. Growth-factor gene therapy for neurodegenerative disorders. Lancet Neurol. 2002;1(1):51–7.

    PubMed  Google Scholar 

  140. Blanchard J, Bolognin S, Chohan MO, Rabe A, Iqbal K, Grundke-Iqbal I. Rescue of synaptic failure and alleviation of learning and memory impairments in a trisomic mouse model of Down syndrome. J Neuropathol Exp Neurol. 2011;70(12):1070–9.

    CAS  PubMed  Google Scholar 

  141. Whittle N, Sartori SB, Dierssen M, Lubec G, Singewald N. Fetal Down syndrome brains exhibit aberrant levels of neurotransmitters critical for normal brain development. Pediatrics. 2007;120(6):e1465–71.

    PubMed  Google Scholar 

  142. Casanova MF, Walker LC, Whitehouse PJ, Price DL. Abnormalities of the nucleus basalis in Down’s syndrome. Ann Neurol. 1985;18(3):310–3.

    CAS  PubMed  Google Scholar 

  143. Granholm AC, Sanders LA, Crnic LS. Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down’s syndrome. Exp Neurol. 2000;161(2):647–63.

    CAS  PubMed  Google Scholar 

  144. Hunter CL, Bimonte HA, Granholm AC. Behavioral comparison of 4 and 6 month-old Ts65Dn mice: age-related impairments in working and reference memory. Behav Brain Res. 2003;138(2):121–31.

    CAS  PubMed  Google Scholar 

  145. Contestabile A, Fila T, Bartesaghi R, Ciani E. Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down’s syndrome and related neurodegenerative diseases. J Neurochem. 2006;97(2):515–26.

    CAS  PubMed  Google Scholar 

  146. Rueda N, Florez J, Martinez-Cue C. Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome. Neurosci Lett. 2008;433(1):22–7.

    CAS  PubMed  Google Scholar 

  147. Chang Q, Gold PE. Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome. Neurobiol Learn Mem. 2008;89(2):167–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. de Souza FM, Busquet N, Blatner M, Maclean KN, Restrepo D. Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome. Sci Rep. 2012;1:137.

    Google Scholar 

  149. Small G, Bullock R. Defining optimal treatment with cholinesterase inhibitors in Alzheimer’s disease. Alzheimers Dement. 2011;7(2):177–84.

    CAS  PubMed  Google Scholar 

  150. Lieberman DN, Mody I. Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature. 1994;369(6477):235–9.

    CAS  PubMed  Google Scholar 

  151. Tong G, Jahr CE. Regulation of glycine-insensitive desensitization of the NMDA receptor in outside-out patches. J Neurophysiol. 1994;72(2):754–61.

    CAS  PubMed  Google Scholar 

  152. Tong G, Shepherd D, Jahr CE. Synaptic desensitization of NMDA receptors by calcineurin. Science. 1995;267(5203):1510–2.

    CAS  PubMed  Google Scholar 

  153. Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, et al. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci USA. 2003;100(15):8987–92.

    CAS  PubMed  Google Scholar 

  154. Rueda N, Llorens-Martin M, Florez J, Valdizan E, Banerjee P, Trejo JL, et al. Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome. J Alzheimers Dis. 2010;21(1):277–90.

    CAS  PubMed  Google Scholar 

  155. Lockrow J, Boger H, Bimonte-Nelson H, Granholm AC. Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome. Behav Brain Res. 2011;221(2):610–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Tolias KF, Bikoff JB, Burette A, Paradis S, Harrar D, Tavazoie S, et al. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron. 2005;45(4):525–38.

    CAS  PubMed  Google Scholar 

  157. Tolias KF, Bikoff JB, Kane CG, Tolias CS, Hu L, Greenberg ME. The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci USA. 2007;104(17):7265–70.

    CAS  PubMed  Google Scholar 

  158. Nishimura T, Yamaguchi T, Tokunaga A, Hara A, Hamaguchi T, Kato K, et al. Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2. Mol Biol Cell. 2006;17(3):1273–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Ultanir SK, Kim JE, Hall BJ, Deerinck T, Ellisman M, Ghosh A. Regulation of spine morphology and spine density by NMDA receptor signaling in vivo. Proc Natl Acad Sci USA. 2007;104(49):19553–8.

    CAS  PubMed  Google Scholar 

  160. Nakazawa T, Kuriu T, Tezuka T, Umemori H, Okabe S, Yamamoto T. Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP. J Neurochem. 2008;105(4):1384–93.

    CAS  PubMed  Google Scholar 

  161. Vastagh C, Gardoni F, Bagetta V, Stanic J, Zianni E, Giampa C, et al. N-methyl-d-aspartate (NMDA) receptor composition modulates dendritic spine morphology in striatal medium spiny neurons. J Biol Chem. 2012;287(22):18103–14.

    CAS  PubMed  Google Scholar 

  162. Marin-Padilla M. Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a Golgi study. Brain Res. 1972;44(2):625–9.

    CAS  PubMed  Google Scholar 

  163. Marin-Padilla M. Pyramidal cell abnormalities in the motor cortex of a child with Down’s syndrome. A Golgi study. J Comp Neurol. 1976;167(1):63–81.

    CAS  PubMed  Google Scholar 

  164. Purpura DP. Normal and aberrant neuronal development in the cerebral cortex of human fetus and young infant. UCLA Forum Med Sci. 1975;18:141–69.

    PubMed  Google Scholar 

  165. Suetsugu M, Mehraein P. Spine distribution along the apical dendrites of the pyramidal neurons in Down’s syndrome. A quantitative Golgi study. Acta Neuropathol. 1980;50(3):207–10.

    CAS  PubMed  Google Scholar 

  166. Takashima S, Becker LE, Armstrong DL, Chan F. Abnormal neuronal development in the visual cortex of the human fetus and infant with Down’s syndrome. A quantitative and qualitative Golgi study. Brain Res. 1981;225(1):1–21.

    CAS  PubMed  Google Scholar 

  167. Dierssen M, Benavides-Piccione R, Martinez-Cue C, Estivill X, Florez J, Elston GN, et al. Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. Cereb Cortex. 2003;13(7):758–64.

    CAS  PubMed  Google Scholar 

  168. Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ, Salehi A, et al. Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. J Comp Neurol. 2004;480(3):281–98.

    PubMed  Google Scholar 

  169. Belichenko PV, Kleschevnikov AM, Salehi A, Epstein CJ, Mobley WC. Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol. 2007;504(4):329–45.

    CAS  PubMed  Google Scholar 

  170. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005;8(8):1051–8.

    CAS  PubMed  Google Scholar 

  171. Roberson R, Toso L, Abebe D, Spong CY. Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model. Am J Obstet Gynecol. 2008;198(3):313e1–4.

    Google Scholar 

  172. Altafaj X, Ortiz-Abalia J, Fernandez M, Potier MC, Laffaire J, Andreu N, et al. Increased NR2A expression and prolonged decay of NMDA-induced calcium transient in cerebellum of TgDyrk1A mice, a mouse model of Down syndrome. Neurobiol Dis. 2008;32(3):377–84.

    CAS  PubMed  Google Scholar 

  173. Yashiro K, Philpot BD. Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology. 2008;55(7):1081–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Incerti M, Toso L, Vink J, Roberson R, Nold C, Abebe D, et al. Prevention of learning deficit in a Down syndrome model. Obstet Gynecol. 2011;117(2 Pt 1):354–61.

    PubMed  Google Scholar 

  175. Busciglio J, Pelsman A, Helguera P, Ashur-Fabian O, Pinhasov A, Brenneman DE, et al. NAP and ADNF-9 protect normal and Down’s syndrome cortical neurons from oxidative damage and apoptosis. Curr Pharm Des. 2007;13(11):1091–8.

    CAS  PubMed  Google Scholar 

  176. Toso L, Cameroni I, Roberson R, Abebe D, Bissell S, Spong CY. Prevention of developmental delays in a Down syndrome mouse model. Obstet Gynecol. 2008;112(6):1242–51.

    PubMed Central  PubMed  Google Scholar 

  177. Hanson JE, Weber M, Meilandt WJ, Wu T, Luu T, Deng L, et al. GluN2B antagonism affects interneurons and leads to immediate and persistent changes in synaptic plasticity, oscillations, and behavior. Neuropsychopharmacology. 2013;38(7):1221–33.

    CAS  PubMed  Google Scholar 

  178. Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am J Med Genet A. 2011;155A(8):1939–48.

    PubMed Central  PubMed  Google Scholar 

  179. Ellis JM, Tan HK, Gilbert RE, Muller DP, Henley W, Moy R, et al. Supplementation with antioxidants and folinic acid for children with Down’s syndrome: randomised controlled trial. BMJ. 2008;336(7644):594–7.

    CAS  PubMed  Google Scholar 

  180. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;(1):CD005593.

  181. Kishnani PS, Sommer BR, Handen BL, Seltzer B, Capone GT, Spiridigliozzi GA, et al. The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome. Am J Med Genet A. 2009;149A(8):1641–54.

    CAS  PubMed  Google Scholar 

  182. Kishnani PS, Heller JH, Spiridigliozzi GA, Lott I, Escobar L, Richardson S, et al. Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10–17. Am J Med Genet A. 2010;152A(12):3028–35.

    PubMed  Google Scholar 

  183. Kondoh T, Kanno A, Itoh H, Nakashima M, Honda R, Kojima M, et al. Donepezil significantly improves abilities in daily lives of female Down syndrome patients with severe cognitive impairment: a 24-week randomized, double-blind, placebo-controlled trial. Int J Psychiatry Med. 2011;41(1):71–89.

    PubMed  Google Scholar 

  184. Costa AC. On the promise of pharmacotherapies targeted at cognitive and neurodegenerative components of Down syndrome. Dev Neurosci. 2011;33(5):414–27.

    CAS  PubMed  Google Scholar 

  185. Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke TA, Goldson EJ, et al. Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl Psychiatry. 2012;2:e141.

    CAS  PubMed Central  PubMed  Google Scholar 

  186. Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci. 1992;106(2):274–85.

    CAS  PubMed  Google Scholar 

  187. Fernandez G, Weyerts H, Schrader-Bolsche M, Tendolkar I, Smid HG, Tempelmann C, et al. Successful verbal encoding into episodic memory engages the posterior hippocampus: a parametrically analyzed functional magnetic resonance imaging study. J Neurosci. 1998;18(5):1841–7.

    CAS  PubMed  Google Scholar 

  188. Alexander MP, Stuss DT, Fansabedian N. California verbal learning test: performance by patients with focal frontal and non-frontal lesions. Brain. 2003;126(Pt 6):1493–503.

    CAS  PubMed  Google Scholar 

  189. Reeves CB, Palmer SL, Reddick WE, Merchant TE, Buchanan GM, Gajjar A, et al. Attention and memory functioning among pediatric patients with medulloblastoma. J Pediatr Psychol. 2006;31(3):272–80.

    PubMed  Google Scholar 

  190. Cherney LR, Halper AS. Performance on the California verbal learning test following right hemisphere stroke: a longitudinal study. Top Stroke Rehabil. 2007;14(1):21–5.

    PubMed  Google Scholar 

  191. Lekeu F, Magis D, Marique P, Delbeuck X, Bechet S, Guillaume B, et al. The California verbal learning test and other standard clinical neuropsychological tests to predict conversion from mild memory impairment to dementia. J Clin Exp Neuropsychol. 2010;32(2):164–73.

    PubMed  Google Scholar 

  192. Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, et al. Memantine for dementia in adults older than 40 years with Down’s syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;379(9815):528–36.

    PubMed  Google Scholar 

  193. Margallo-Lana ML, Ballard C, Morris C, Kay D, Tyrer S, Moore B. Cognitive decline in Down syndrome. Arch Neurol. 2003;60(7):1024 (author reply).

  194. Costa AC. Alzheimer disease: treatment of Alzheimer disease in Down syndrome. Nat Rev Neurol. 2012;8(4):182–4.

    CAS  PubMed  Google Scholar 

  195. Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011;3(64):64ra1.

    Google Scholar 

  196. Krab LC, de Goede-Bolder A, Aarsen FK, Pluijm SM, Bouman MJ, van der Geest JN, et al. Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA. 2008;300(3):287–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  197. de Vries PJ. Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics. 2010;7(3):275–82.

    PubMed  Google Scholar 

  198. Xie W, Ramakrishna N, Wieraszko A, Hwang YW. Promotion of neuronal plasticity by (–)-epigallocatechin-3-gallate. Neurochem Res. 2008;33(5):776–83.

    CAS  PubMed  Google Scholar 

  199. Mazur-Kolecka B, Golabek A, Kida E, Rabe A, Hwang YW, Adayev T, et al. Effect of DYRK1A activity inhibition on development of neuronal progenitors isolated from Ts65Dn mice. J Neurosci Res. 2012;90(5):999–1010.

    CAS  PubMed  Google Scholar 

  200. Guidi S, Stagni F, Bianchi P, Ciani E, Ragazzi E, Trazzi S, et al. Early pharmacotherapy with fluoxetine rescues dendritic pathology in the Ts65Dn mouse model of Down syndrome. Brain Pathol. 2013;23:129–43.

    CAS  PubMed  Google Scholar 

  201. Vidal V, Garcia S, Martinez P, Corrales A, Florez J, Rueda N, et al. Lack of behavioral and cognitive effects of chronic ethosuximide and gabapentin treatment in the Ts65Dn mouse model of Down syndrome. Neuroscience. 2012;220:158–68.

    CAS  PubMed  Google Scholar 

  202. Moon J, Chen M, Gandhy SU, Strawderman M, Levitsky DA, Maclean KN, et al. Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome. Behav Neurosci. 2010;124(3):346–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  203. Hunter CL, Bachman D, Granholm AC. Minocycline prevents cholinergic loss in a mouse model of Down’s syndrome. Ann Neurol. 2004;56(5):675–88.

    CAS  PubMed  Google Scholar 

  204. Fukuda Y, Berry TL, Nelson M, Hunter CL, Fukuhara K, Imai H, et al. Stimulated neuronal expression of brain-derived neurotrophic factor by neurotropin. Mol Cell Neurosci. 2010;45(3):226–33.

    CAS  PubMed  Google Scholar 

  205. Vink J, Incerti M, Toso L, Roberson R, Abebe D, Spong CY. Prenatal NAP + SAL prevents developmental delay in a mouse model of Down syndrome through effects on N-methyl-d-aspartic acid and gamma-aminobutyric acid receptors. Am J Obstet Gynecol. 2009;200(5):524 e1–4.

    Google Scholar 

  206. Braudeau J, Dauphinot L, Duchon A, Loistron A, Dodd RH, Herault Y, et al. Chronic treatment with a promnesiant GABA-A alpha5-selective inverse agonist increases immediate early genes expression during memory processing in mice and rectifies their expression levels in a down syndrome mouse model. Adv Pharmacol Sci. 2011;2011:153218.

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Braudeau J, Delatour B, Duchon A, Pereira PL, Dauphinot L, de Chaumont F, et al. Specific targeting of the GABA-A receptor alpha5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice. J Psychopharmacol. 2011;25(8):1030–42.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank the following funding agencies: The Colorado Clinical and Translational Institute (CCTSI), Instituto Alana, and The Forest Research Institute (for the Investigator Initiated Grant NAM-58). The authors would also like to thank Jonathan P. Scott-McKean for the artwork of Fig. 1. Authors state that they have no conflict of interest.

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  1. Division of Pediatric Neurology, Department of Pediatrics, Case Western Reserve School of Medicine and Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Mail Stop RBC 6090, Cleveland, OH, 44106, USA

    Alberto C. S. Costa & Jonah J. Scott-McKean

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Costa, A.C.S., Scott-McKean, J.J. Prospects for Improving Brain Function in Individuals with Down Syndrome. CNS Drugs 27, 679–702 (2013). https://doi.org/10.1007/s40263-013-0089-3

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