Cognitive and pharmacological insights from the Ts65Dn mouse model of Down syndrome

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Down syndrome (DS) is a multi-faceted condition resulting in the most common genetic form of intellectual disability. Mouse models of DS, especially the Ts65Dn model, have been pivotal in furthering our understanding of the genetic, molecular and neurobiological mechanisms that underlie learning and memory impairments in DS. Cognitive and pharmacological insights from the Ts65Dn mouse model have led to remarkable translational progress in the development of therapeutic targets and in the emergence of DS clinical trials. Unravelling the pathogenic role of trisomic genes on human chromosome 21 and the genotype–phenotype relationship still remains a pertinent goal for tackling cognitive deficits in DS.

Highlights

► DS causes perturbed synaptic plasticity and excessive inhibitory neurotransmission. ► Ts65Dn mouse model recapitulates behavioural and cognitive phenotypes of DS. ► Several triplicated Hsa21-associated genes in Ts65Dn mice are implicated. ► Insights from Ts65Dn have led to pharmacological interventions and clinical trials.

Introduction

Trisomy of human chromosome 21 (Hsa21) causes overexpression of more than 500 genes, resulting in the multi-faceted genetic condition characterised as Down syndrome (DS) [1, 2]. With an incidence of approximately one in 650–1000 live births worldwide, DS is the most common genetic form of intellectual disability [3]. Accelerated and precocious aging occurs in DS, as does early-onset Alzheimer's disease (AD), which is manifested in over 75% of people with DS by the age of 65 [3, 4, 5•]. Learning and memory impairments in DS are marked by perturbed neurodevelopment, altered neuronal structure, and synaptic plasticity deficits. The cognitive profiles in DS vary in both expressivity and severity; conceivably from allelic differences in Hsa21 genes and the complex interplay with other non-Hsa21 genes, epigenetic influences and environmental factors. Understanding these genotype–phenotype correlations may help develop pharmacological interventions. Mouse models of DS, including the Ts65Dn mouse, recapitulate many cognitive phenotypes of DS and have been instrumental in elucidating the molecular pathogenesis underlying DS, mapping Hsa21 genes to various phenotypes, and assessing the effect of potential therapeutic targets [6, 7, 8]. Herein, we highlight recent insights obtained from the Ts65Dn mouse model to unravel mechanisms of learning and memory impairments in DS; and how these findings have led to recent breakthroughs in pharmacological interventions.

Section snippets

Neurodevelopment

Neurodevelopment is perturbed in DS as demonstrated by a reduced brain volume, reduced number of neurons, and abnormal neuronal morphology in several brain regions; particularly the granule cells in the cerebellar cortex [9]. Compared to healthy infants, brains of DS infants show an increase in total dendritic branching and higher total dendritic length, which then steadily decreases to lower than normal levels during adolescence and into adulthood. These structural and dendritic differences

Pharmacological insights from the Ts65Dn mouse

The identification of behavioural, morphological, and neurobiological alterations in the Ts65Dn mouse model have led to invaluable insights into the pathogenesis of DS that allow for potential therapeutic targets to be explored (Table 2).

Conclusion

Triplication of Hsa21 genes leads to a plethora of multi-system pathologies that characterise DS, rendering it complex to understand. Despite this, since the discovery of DS in the 19th century, the life expectancy of people with DS has increased from an average age of 12 years old in the 1940s to 60 years of age at present owing to dramatic advances in medical treatment and social intervention [3]. Mouse models of DS, especially the Ts65Dn mouse, have provided an unequivocal contribution to

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

We thank the Brain Research Trust for funding (A.R.). We also thank NIH (PN2 EY016525; R01 NS066072-01A1; R01 NS055371; R01 NS24054), Down Syndrome Research and Treatment Foundation, Alzhiemer's Association, Thrasher Research Fund and the Larry L. Hillblom Foundation for funding (W.C.M.).

References (60)

  • M. Hanney 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)
  • M.M. Ahmed et al.

    Loss of correlations among proteins in brains of the Ts65Dn mouse model of Down syndrome

    J Proteome Res

    (2012)
  • M. Hattori et al.

    The DNA sequence of human chromosome 21

    Nature

    (2000)
  • A.H. Bittles et al.

    The four ages of Down syndrome

    Eur J Public Health

    (2007)
  • A. Coppus et al.

    Dementia and mortality in persons with Down's syndrome

    J Intellect Disabil Res

    (2006)
  • F. Beacher et al.

    Brain anatomy and ageing in non-demented adults with Down's syndrome: an in vivo MRI study

    Psychol Med

    (2010)
  • R.H. Reeves et al.

    A mouse model for Down syndrome exhibits learning and behaviour deficits

    Nat Genet

    (1995)
  • M.T. Davisson et al.

    Segmental trisomy as a mouse model for Down syndrome

    Prog Clin Biol Res

    (1993)
  • A. Ruparelia et al.

    Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

    J Biomed Res

    (2010)
  • I.T. Lott et al.

    Cognitive deficits and associated neurological complications in individuals with Down's syndrome

    Lancet Neurol

    (2010)
  • R.J. Roper et al.

    A neural crest deficit in Down syndrome mice is associated with deficient mitotic response to Sonic hedgehog

    Mech Dev

    (2009)
  • A. O’Doherty et al.

    An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes

    Science

    (2005)
  • N. Micali et al.

    Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress

    Nucleic Acids Res

    (2010)
  • J. Busciglio et al.

    Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro

    Nature

    (1995)
  • E.S. Ang et al.

    Four-dimensional migratory coordinates of GABAergic interneurons in the developing mouse cortex

    J Neurosci

    (2003)
  • J.G. Corbin et al.

    Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain

    Nat Neurosci

    (2001)
  • T.F. Haydar et al.

    Trisomy 21 and early brain development

    Trends Neurosci

    (2011)
  • P.V. Belichenko et al.

    Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome

    J Comp Neurol

    (2004)
  • A.M. Kleschevnikov et al.

    Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome

    J Neurosci

    (2004)
  • P.V. Belichenko et al.

    Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome

    J Comp Neurol

    (2009)
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