Cognitive and pharmacological insights from the Ts65Dn mouse model of Down syndrome
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)
- et al.
Cell cycle elongation impairs proliferation of cerebellar granule cell precursors in the Ts65Dn mouse, an animal model for Down syndrome
Brain Pathol
(2009) - et al.
Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice
Proc Natl Acad Sci USA
(2006) - et al.
Proliferation deficits and gene expression dysregulation in Down's syndrome (Ts1Cje) neural progenitor cells cultured from neurospheres
J Neurosci Res
(2009) - et al.
Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer's disease
J Neurochem
(2011) - et al.
Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome
Nat Neurosci
(2010) - et al.
Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current
J Neurophysiol
(2007) - et al.
NMDA-mediated regulation of DSCAM dendritic local translation is lost in a mouse model of Down's syndrome
J Neurosci
(2010) - et al.
Modulatory role of drebrin on the cytoskeleton within dendritic spines in the rat cerebral cortex
J Neurosci
(1996) - et al.
Protective peptides that are orally active and mechanistically nonchiral
J Pharmacol Exp Ther
(2004) - et al.
Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome
Neurosci Lett
(2008)