Brain Structure and Function

, Volume 221, Issue 9, pp 4337–4352 | Cite as

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome

  • Brian E. Powers
  • Ramon Velazquez
  • Christy M. Kelley
  • Jessica A. Ash
  • Myla S. Strawderman
  • Melissa J. Alldred
  • Stephen D. Ginsberg
  • Elliott J. Mufson
  • Barbara J. StruppEmail author
Original Article


Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer’s disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs.


Down syndrome Aging Attention Basal forebrain cholinergic neurons Choline acetyltransferase Trisomic mice 



Supported by National Institute of Child Health and Human Development, Grant number HD057564 (to BJS, EJM, SDG); National Institute on Aging, Grant numbers AG014449 (to EJM, SDG) and AG043375 (EJM & SDG); the Alzheimer’s Association, Grant number IIRG-12-237253 (to SDG); and the National Institute of Health, Grant number HD45224.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.


  1. Abrous DN, Wojtowics JM (2008) 21 Neurogenesis and hippocampal memory system. Cold Spring Harb Mongraph Arch North Am 52:445–461Google Scholar
  2. Aimone JB, Wiles J, Gage FH (2006) Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci 9:723–727CrossRefPubMedGoogle Scholar
  3. Antonarakis SE, Lyle R, Chrast R, Scott HS (2001) Differential gene expression studies to explore the molecular pathophysiology of Down syndrome. Brain Res Brain Res Rev 36:265–274CrossRefPubMedGoogle Scholar
  4. Ash JA, Velazquez R, Kelley CM, Powers BE, Strawderman M, Mufson EJ et al (2014) Perinatal choline supplementation improves spatial mapping and increases cholinergic basal forebrain cholinergic neuron number and size in aged Ts65Dn mice. Neurobiol Dis 70:32–42CrossRefPubMedPubMedCentralGoogle Scholar
  5. Berardi A, Parasuraman R, Haxby JV (2001) Overall vigilance and sustained attention decrements in healthy aging. Exp Aging Res 27:19–39CrossRefPubMedGoogle Scholar
  6. Bianchi P, Ciani E, Guidi S, Trazzi S, Felice D, Grossi G et al (2010) Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome. J Neurosci 30:8769–8779CrossRefPubMedGoogle Scholar
  7. Bowes C, Li T, Frankel WN, Danciger M, Coffin JM, Applebury ML, Farber DB (1993) Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase. Proc Natl Acad Sci USA 90:2955–2959CrossRefPubMedPubMedCentralGoogle Scholar
  8. Brown JH, Johnson MH, Paterson SJ, Gilmore R, Longhi E, Karmiloff-Smith A (2003) Spatial representation and attention in toddlers with Williams syndrome and Down syndrome. Neuropsychologia 41:1037–1046CrossRefPubMedGoogle Scholar
  9. Capone GT (2001) Down syndrome: advances in molecular biology and the neurosceinces. J Dev Behav Pediatr 22:40–59CrossRefPubMedGoogle Scholar
  10. Casanova MF, Walker LC, Whitehouse PJ, Price DL (1985) Abnormalities of the nucleus basalis in Down’s syndrome. Ann Neurol 18:310–313CrossRefPubMedGoogle Scholar
  11. Centers for Disease Control and Prevention (2006) Improved national prevalence estimates for 18 selected major birth defects—United States, 1999–2001. Morb Mortal Wkly Rep 54:1301–1305Google Scholar
  12. Clark D, Wilson GN (2003) Behavioral assessment of children with Down syndrome using the Reiss psychopathology scale. Am J Med Genet A 118:210–216CrossRefGoogle Scholar
  13. Colas D, Chuluun B, Warrier D, Blank M, Wetmore DZ, Buckmaster P, Garner CC, Heller HC (2013) Short-term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down’s syndrome. Br J Pharmacol 169(5):963–973CrossRefPubMedPubMedCentralGoogle Scholar
  14. Contestabile A, Fila T, Bartesaghi R, Contestabile A, Ciani E (2006) Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down’s syndrome and related neurodegenerative diseases. J Neurochem 97(2):515–526CrossRefPubMedGoogle Scholar
  15. Cooper JD, Salehi A, Delcroix JD, Howe CL, Belichenko PV, Chua-Couzens J et al (2001) 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 98:10439–10444CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cornish K, Scerif G, Karmiloff-Smith A (2007) Tracing syndrome-specific trajectories of attention across the lifespan. Cortex 43:672–685CrossRefPubMedGoogle Scholar
  17. Das I, Reeves R (2011) The use of mouse models to understand and improve cognitive deficits in Down syndrome. Dis Model Mech 4:596–606CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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 360:263–280PubMedGoogle Scholar
  19. Davisson MT, Schmidt C, Reeves RH, Irving NG, Akeson EC, Harris BS, Bronson RT (1993) Segmental trisomy as a mouse model for Down syndrome. Prog Clin Biol Res 384:117–133PubMedGoogle Scholar
  20. Della Sala S, Laiacona M, Spinnler H, Ubezio C (1992) A cancellation test: its reliability in assessing attentional deficits in Alzheimer’s disease. Psychol Med 22:885–901CrossRefPubMedGoogle Scholar
  21. Driscoll LL, Carroll JC, Moon J, Crnic LS, Levitsky DA, Strupp BJ (2004) Impaired sustained attention and error-induced stereotypy in the aged Ts65Dn mouse: a mouse model of Down syndrome and Alzheimer’s disease. Behav Neurosci 118:1196–1205CrossRefPubMedGoogle Scholar
  22. Faizi M, Bader PL, Tun C, Encarnacion A, Kleschevnikov A, Belichenko P, Saw N, Priestly M, Tsien RW, Mobley WC, Shamloo M (2011) Comprehensive behavioral phenotyping on Ts65Dn mouse model of Down syndrome: activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer. Neurobiol Dis 43(2):397–413CrossRefPubMedPubMedCentralGoogle Scholar
  23. Foster JK (2001) Seclective attention in Alzheimer’s disease. Front Biosci 6:D135–D153PubMedGoogle Scholar
  24. Fuchs C, Ciani E, Guidi S, Trazzi S, Bartesaghi R (2012) Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression. Lab Invest 92:1648–1660CrossRefPubMedGoogle Scholar
  25. Granholm AC, Sanders LA, Crnic LS (2000) Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down’s syndrome. Exp Neurol 161:647–663CrossRefPubMedGoogle Scholar
  26. Granholm AC, Ford KA, Hyde LA, Bimonte HA, Hunter CL, Nelson M et al (2002) Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome. Physiol Behav 77(2–3):371–385CrossRefPubMedGoogle Scholar
  27. Greenwood PM, Parasuraman R, Alexander GE (1997) Controlling the focus of spatial attention during visual search: effects of advanced aging and Alzheimer disease. Neuropsychology 11:3–12CrossRefPubMedGoogle Scholar
  28. Guidi S, Ciani E, Bonasoni P, Santini D, Bartesaghi R (2011) Widespread proliferation impairment and hypocellularity in the cerebellum of fetuses with Down syndrome. Brain Pathol 21:361–373CrossRefPubMedGoogle Scholar
  29. Gundersen HJ (1988) The nucleator. J Microsc 151:3–21CrossRefPubMedGoogle Scholar
  30. Gundersen HJ, Jensen EB, Kieu K, Nielsen J (1999) The efficiency of systematic sampling in stereology—reconsidered. J Microsc 193:199–211CrossRefPubMedGoogle Scholar
  31. Hasselmo ME, Sarter M (2011) Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology 36:52–73CrossRefPubMedGoogle Scholar
  32. Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE et al (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci USA 93:13333–13338CrossRefPubMedPubMedCentralGoogle Scholar
  33. Hyde LA, Crnic LS (2001) Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer’s disease. Behav Neurosci 115:1239–1246CrossRefPubMedGoogle Scholar
  34. Hyde LA, Frisone DF, Crnic LS (2001) Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function. Behav Brain Res 118:53–60CrossRefPubMedGoogle Scholar
  35. Iacono D, O’Brien R, Resnick SM, Zonderman AB, Pletnikova O, Rudow G et al (2008) Neuronal hypertrophy in asymptomatic Alzheimer disease. J Neuropathol Exp Neurol 67(6):578–589CrossRefPubMedPubMedCentralGoogle Scholar
  36. Isacson O, Seo H, Lin L, Albeck D, Granholm AC (2002) Alzheimer’s disease and Down’s syndrome: roles of APP, trophic factors and ACh. Trends Neurosci 25:79–84CrossRefPubMedGoogle Scholar
  37. Jones DN, Barnes JC, Kirkby DL, Higgins GA (1995) Age-associated impairments in a test of attention: evidence for involvement of cholinergic systems. J Neurosci 15:7282–7292PubMedGoogle Scholar
  38. Kaur G, Sharma A, Xu W, Gerum S, Alldred MJ, Subbanna S, Basavarajappa BS, Pawlik M, Ohno M, Ginsberg SD et al (2014) Glutamatergic transmission aberration: a major cause of behavioral deficits in a murine model of Down’s syndrome. J Neurosci 34:5099–5106CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kelley CM, Powers BE, Velazquez R, Ash JA, Ginsberg SD, Strupp BJ, Mufson EJ (2014a) Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice. J Comp Neurol 522:1390–1410CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kelley CM, Powers BE, Velazquez R, Ash JA, Ginsberg SD, Strupp BJ, Mufson EJ (2014b) Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease. Brain Pathol 24:33–44CrossRefPubMedGoogle Scholar
  41. Kelley CM, Ash JA, Powers BE, Velazquez R, Alldred MJ, Ikonomovic MD, Ginsberg SD, Strupp BJ, Mufson EJ (2016) Effects of maternal choline supplementation on the septohippocampal cholinergic system in the Ts65Dn mouse model of Down syndrome. Curr Alzheimer Res 13(1):77–89Google Scholar
  42. Krinsky-McHale SJ, Devenny DA, Kittler P, Silverman W (2008) Selective attention deficits associated with mild cognitive impairment and early stage Alzheimer’s disease in adults with Down syndrome. Am J Ment Retard 113:369–386CrossRefPubMedGoogle Scholar
  43. Lai F, Williams RS (1989) A prospective study of Alzheimer disease in Down syndrome. Arch Neurol 46:849–853CrossRefPubMedGoogle Scholar
  44. Leuner B, Gould E, Shors TJ (2006) Is there a link between adult neurogenesis and learning? Hippocampus 16:216–224CrossRefPubMedGoogle Scholar
  45. Levinoff EJ, Li KZ, Murtha S, Chertkow H (2004) Selective attention impairments in Alzheimer’s disease: evidence for dissociable components. Neuropsychology 18:580–588CrossRefPubMedGoogle Scholar
  46. Lledo P-M, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193CrossRefPubMedGoogle Scholar
  47. Lockrow J, Prakasam A, Huang P, Bimonte-Nelson H, Sambamurti K, Granholm AC (2009) Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model. Exp Neurol 216:278–289CrossRefPubMedGoogle Scholar
  48. Lockrow J, Boger H, Bimonte-Nelson H, Granholm AC (2011) Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome. Behav Brain Res 221:610–622CrossRefPubMedGoogle Scholar
  49. Mann DM (1988) Alzheimer’s disease and Down’s syndrome. Histopathology 13:125–137CrossRefPubMedGoogle Scholar
  50. Mann DM, Lincoln J, Yates PO, Brennan CM (1980) Monoamine metabolism in Down syndrome. Lancet 2:1366–1367CrossRefPubMedGoogle Scholar
  51. Mann DM, Yates PO, Marcyniuk B, Ravindra CR (1986) The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol 12:447–457CrossRefPubMedGoogle Scholar
  52. McGaughy J, Sarter M (1995) Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology 117:340–357CrossRefPubMedGoogle Scholar
  53. Mesulam MM, Mufson EJ, Wainer BH, Levey AL (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:185–201CrossRefGoogle Scholar
  54. Moon J, Chen M, Gandhy SU, Strawderman M, Levitsky DA, Maclean KN, Strupp BJ (2010) Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome. Behav Neurosci 124:346–361CrossRefPubMedPubMedCentralGoogle Scholar
  55. Mufson EJ, Bothwell M, Kordower JH (1989) Loss of nerve growth factor receptor-containing neurons in Alzheimer’s disease: a quantitative analysis across subregions of the basal forebrain. Exp Neurol 105:221–232CrossRefPubMedGoogle Scholar
  56. Mufson EJ, Ma SY, Cochran EJ, Bennett DA, Beckett LA, Jaffar S, Saragovi HU, Kordower JH (2000) Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 427:19–30CrossRefPubMedGoogle Scholar
  57. Muir JL, Fischer W, Bjorklund A (1999) Decline in visual attention and spatial memory in aged rats. Neurobiol Aging 20:605–615CrossRefPubMedGoogle Scholar
  58. Mural RJ, Adams MD, Myers EW, Smith HO, Miklos GL, Wides R et al (2002) A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome. Science 296:1661–1671CrossRefPubMedGoogle Scholar
  59. Parasuraman R, Giambra L (1991) Skill development in vigilance: effects of event rate and age. Psychol Aging 6:155–169CrossRefPubMedGoogle Scholar
  60. Parker SE, Mai CT, Canfield M, Rickard R, Wang Y, Meyer RE et al (2010) Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004–2006. Birth Defects Res A Clin Mol Teratol 88(12):1008–1016CrossRefPubMedGoogle Scholar
  61. Patterson D, Costa ACS (2005) Down syndrome and genetics—a case of linked histories. Nat Rev Genet 6:137–147CrossRefPubMedGoogle Scholar
  62. Pignatti R, Rabuffetti M, Imbornone E, Mantovani F, Alberoni M, Farina E, Canal N (2005) Specific impairments of selective attention in mild Alzheimer’s disease. J Clin Exp Neuropsychol 27:436–448CrossRefPubMedGoogle Scholar
  63. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS et al (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet 11:177–184CrossRefPubMedGoogle Scholar
  64. Rueda N, Florez J, Martinez-Cue C (2012) Mouse models of Down syndrome as a tool to unravel the causes of mental disabilities. Neural Plast 2012:584071PubMedPubMedCentralGoogle Scholar
  65. Rye DB, Wainer BH, Mesulam MM, Mufson EJ, Saper CB (1984) Cortical projections arising from the basal forebrain: a study of cholinergic and noncholinergic components employing combined retrograde tracing and immunohistochemical localization of choline acetyltransferase. Neuroscience 13:627–643CrossRefPubMedGoogle Scholar
  66. Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS et al (2006) Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51:29–42CrossRefPubMedGoogle Scholar
  67. Sarter M, Bruno JP (1997) Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 23:28–46CrossRefPubMedGoogle Scholar
  68. Sendera TJ, Ma SY, Jaffar S, Kozlowski PB, Kordower JH, Mawal Y et al (2000) Reduction in TrkA-immunoreactive neurons is not associated with an overexpression of galaninergic fibers within the nucleus basalis in Down’s syndrome. J Neurochem 74:1185–1196CrossRefPubMedGoogle Scholar
  69. Seo H, Isacson O (2005) Abnormal APP, cholinergic and cognitive function in Ts65Dn Down’s model mice. Exp Neurol 193:469–480CrossRefPubMedGoogle Scholar
  70. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376CrossRefPubMedGoogle Scholar
  71. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E (2002) Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12:578–584CrossRefPubMedPubMedCentralGoogle Scholar
  72. Sofroniew MV, Galletly NP, Isacson O, Svendsen CN (1990) Survival of adult basal forebrain cholinergic neurons after loss of target neurons. Science 247:338–342CrossRefPubMedGoogle Scholar
  73. Sturgeon X, Gardiner KJ (2011) Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions. Mamm Genome 22:261–271CrossRefPubMedGoogle Scholar
  74. Tomporowski PD, Hayden AM, Applegate B (1990) Effects of background event rate on sustained attention of mentally retarded and nonretarded adults. Am J Ment Retard 94:499–508PubMedGoogle Scholar
  75. Velazquez R, Ash JA, Powers BE, Kelley CM, Strawderman M, Luscher ZI et al (2013) Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis 58:92–101CrossRefPubMedPubMedCentralGoogle Scholar
  76. Visser FE, Aldenkamp AP, van Huffelen AC, Kuilman M, Overweg J, van Wijk J (1997) Prospective study of the prevalence of Alzheimer-type dementia in institutionalized individuals with Down syndrome. Am J Ment Retard 101:400–412PubMedGoogle Scholar
  77. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215:1237–1239CrossRefPubMedGoogle Scholar
  78. Wilding J, Cornish K, Munir F (2002) Further delineation of the executive deficit in males with fragile-X syndrome. Neuropsychologia 40:1343–1349CrossRefPubMedGoogle Scholar
  79. Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM (1985a) Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology 35:957–961CrossRefPubMedGoogle Scholar
  80. Wisniewski KE, Wisniewski HM, Wen GY (1985b) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17:278–282CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Brian E. Powers
    • 1
  • Ramon Velazquez
    • 1
  • Christy M. Kelley
    • 2
  • Jessica A. Ash
    • 1
  • Myla S. Strawderman
    • 1
  • Melissa J. Alldred
    • 3
    • 4
  • Stephen D. Ginsberg
    • 3
    • 4
    • 5
  • Elliott J. Mufson
    • 6
  • Barbara J. Strupp
    • 1
    Email author
  1. 1.Division of Nutritional Sciences and Department of PsychologyCornell UniversityIthacaUSA
  2. 2.Division of Neurological SciencesRush University Medical CenterChicagoUSA
  3. 3.Center for Dementia ResearchNathan Kline InstituteOrangeburgUSA
  4. 4.Department of PsychiatryNew York University Langone Medical CenterNew YorkUSA
  5. 5.Department of Neuroscience and PhysiologyNew York University Langone Medical CenterNew YorkUSA
  6. 6.Division of NeurobiologyBarrow Neurological InstitutePhoenixUSA

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