Communication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome

https://doi.org/10.1016/j.pneurobio.2010.01.003Get rights and content

Abstract

Down syndrome (DS) is the leading cause of genetically-defined intellectual disability and congenital birth defects. Despite being one of the first genetic diseases identified, only recently, thanks to the phenotypic analysis of DS mouse genetic models, we have begun to understand how trisomy may impact cognitive function. Cognitive disabilities in DS appear to result mainly from two pathological processes: neurogenesis impairment and Alzheimer-like degeneration. In DS brain, suboptimal network architecture and altered synaptic communication arising from neurodevelopmental impairment are key determinants of cognitive defects. Hypocellularity and hypoplasia start at early developmental stages and likely depend upon impaired proliferation of neuronal precursors, resulting in reduction of numbers of neurons and synaptic contacts. The impairment of neuronal precursor proliferation extends to adult neurogenesis and may affect learning and memory. Neurodegenerative mechanisms also contribute to DS cognitive impairment. Early onset Alzheimer disease occurs with extremely high incidence in DS patients and is causally-related to overexpression of β-amyloid precursor protein (βAPP), which is one of the triplicated genes in DS. In this review, we will survey the available findings on neurodevelopmental and neurodegenerative changes occurring in DS throughout life. Moreover, we will discuss the potential mechanisms by which defects in neurogenesis and neurodegenerative processes lead to altered formation of neural circuits and impair cognitive function, in connection with findings on pharmacological treatments of potential benefit for DS.

Introduction

Down syndrome (DS), the most common genetic form of intellectual disability, was first described by John Langdon Down about 150 years ago (1866). DS occurs in 1 every 700–800 live births and epidemiologic data give an estimated incidence of more than 200,000 cases per year worldwide (Christianson et al., 2006). This may represent an underestimation when considering that DS occurs in about 2% of spontaneous abortions (Hsu, 1998). The only known risk factor for DS is increased meiotic maternal non-disjunction errors occurring with age (Hassold and Hunt, 2001). Life expectancy of DS individuals is generally shorter with respect to the normal population and varies with the severity of the phenotype. However, in the past decades, due to enhanced medical and social care, the survival rate of DS people has greatly improved, increasing from 12 years of age in 1940s to the current 60 years and over (Bittles et al., 2006, Bittles and Glasson, 2004, Glasson et al., 2002, Roizen and Patterson, 2003).

Nearly a century after its first description, genetic studies by Lejeune et al., 1959 demonstrated that DS is caused by trisomy of chromosome 21 (HSA21). In some cases, DS individuals carry only a partial trisomy of chromosome 21 and show variable phenotypes. Indeed, cytogenetic and phenotypic studies of such cases have defined chromosomal regions associated with distinct features and, in some cases, the gene(s) responsible for specific DS phenotypes. Specifically, the distal part of the long arm of HSA21 has been identified as “Down syndrome critical region” (DSCR) and has been associated with development of cognitive disabilities (Delabar et al., 1993, Korenberg et al., 1994, Rahmani et al., 1989).

Different theories have been proposed to explain how triplication of HSA21 leads to DS. The “dosage imbalance hypothesis” states that the increased dosage of HSA21 genes (i.e., dosage-sensitive genes) is the direct cause of the phenotypical alterations of DS (Antonarakis et al., 2001, Antonarakis et al., 2004, Pritchard and Kola, 1999). An alternative view is the “amplified developmental instability hypothesis”, which postulates that the non-specific triplication of a relative small number of genes causes genetic imbalance with wide impact on global gene expression and on the regulation of intracellular signaling pathways, leading to deleterious effects on development (Hall, 1965, Moldrich, 2007, Pritchard and Kola, 1999, Shapiro, 1983). A synthesis of these opposite visions argues that in the trisomy-driven deregulated scenario, some dosage-sensitive genes, whose triplication per se would have only modest effects, may account for the plethora of DS phenotypes (Olson et al., 2004a, Roper and Reeves, 2006). This view is embodied by findings in animal models of DS. For example, Ts1Rhr mice that are trisomic only for the mouse chromosome segment orthologous to human DSCR do not show skull and mandible abnormalities typical of other DS mouse models with larger triplication (i.e., Ts65Dn mice), indicating that DSCR alone is not sufficient to produce this phenotype. On the other hand, when DSCR is returned to two copies in Ts65Dn mice the craniofacial defects are largely attenuated indicating that the triplication of genes from the DSCR region contribute to this phenotype only in combination with other triplicated genes (Olson et al., 2004a).

Numerous developmental defects are associated with Down syndrome (Antonarakis and Epstein, 2006, Delabar et al., 2006), including skeletal defects, brachycephaly, craniofacial dysmorphic features, defects of atrioventricular septum, valve stenosis and abnormalities of the gastrointestinal system (Delabar et al., 2006). Alterations of brain development and intellectual disabilities invariably occur in trisomy 21 (Devenny et al., 2000, Devenny et al., 1996, Devenny et al., 2005, Krinsky-McHale et al., 2002, Nelson et al., 2005). Although at the neuropathological level virtuallly all DS subjects develop neurodegenerative changes typical of Alzheimer disease (AD) during adulthood (Ball and Nuttall, 1980, Folin et al., 2003, Hof et al., 1995, Holland et al., 2000, Lott and Head, 2005, Nadel, 2003), only a proportion of cases develop dementia-related cognitive decline (Devenny et al., 1996, Devenny et al., 2005)

In this review, we will survey available findings on the neurodevelopmental and neurodegenerative changes occurring in DS throughout life. In particular, we will discuss how defects in neurogenesis and neurodegenerative processes alter neural circuit formation and impair cognitive functions. Although a direct relationship between the neurodevelopmental impairment and neurodegeneration has not been proven so far, it is likely that some common pathways underlie these processes. DS-associated neurodegenerative mechanisms and neurodevelopmental abnormalities will be discussed in connection with the identification of new pharmacological treatments of potential benefit for DS.

Section snippets

Cognitive dysfunction in DS: from neurodevelopmental abnormalities to neurodegeneration

Intellectual disabilities are the most striking feature of DS. The Intelligence Quotient (IQ) of DS individuals range from 30 to 70 with an average value of 50 (Vicari, 2004, Vicari et al., 2000, Vicari et al., 2005). Diverse cognitive domains are differentially affected by the syndrome. In DS children and adults some domains (e.g., vocabulary and adaptive skills) develop at a faster rate than others (e.g., memory and executive function). However, the overall learning rate decreases and results

Neuroanatomical correlates of DS cognitive impairment

Several studies have focused on elucidating the neuroanatomical correlates of DS cognitive impairment. There is strong evidence that the volume of DS brain is reduced. Indeed, brains of adult DS individuals are consistently smaller (>20% reduction) as compared to healthy subjects, even when the measure is corrected for the reduced body size characteristic of the syndrome (Kemper, 1991). These differences appear during gestation and increase postnatally. In fact, ultrasonographical data and

Cognitive and neuromorphological changes typical of DS in animal models of human trisomy 21

Numerous mouse models replicating human trisomy 21 to various extent have been created (Table 1; reviewed in Antonarakis et al., 2004, Delabar et al., 2006, Moore and Roper, 2007, Rachidi and Lopes, 2007). The long arm of human chromosome 21 contains genes that are homologous to synthenic regions of mouse chromosomes 16, 17 and 10 (Gardiner et al., 2003, Nikolaienko et al., 2005) and have their conserved orthologs in the distal end of murine chromosome 16 (MMU16; Fig. 1) (Antonarakis et al.,

Synaptic correlates of DS cognitive impairment

As previously mentioned, defective hippocampus-related functions underlie several cognitive disabilities in DS subjects (Pennington et al., 2003) and in DS mouse models. The hippocampal system is fundamental for learning and memory and is the site of different forms of long-term synaptic plasticity that are crucial for memory formation, consolidation, retrieval and reconsolidation. Within this context, morphological alterations of hippocanpal dendritic spines found in DS mouse models indicate

Faulty neurogenesis and neurodevelopmental abnormalities in DS

Emerging evidence indicates that impaired cell proliferation during development is a major determinant of reduced brain volume and intellectual disabilities in DS (Contestabile et al., 2007, Guidi et al., 2008). This hypothesis initially emerged from observations showing reduced telencephalic size and delayed cortical layer expansion in Ts16 mice (Haydar et al., 1996). Such phenotype is apparently due to decreased numbers of neocortical founder cells, slight elongation of their cell cycle,

Molecular mechanisms of neurodevelopmental deficits and neurodegenerative processes in DS

Data summarized above and in Fig. 4 clearly indicate that in DS mouse models morphological and functional alterations of synaptic connections and network activity arise from abnormal neurogenesis and exacerbate with aging due to neurodegenerative processes. Several proteins expressed by triplicated HSA21 genes have been shown to contribute to such complex scenario by altering intracellular pathways crucial for neuronal development, synaptic activity and neuronal survival (Benavides-Piccione et

Therapeutic strategies for DS: perspective for the future

The increasing knowledge of pathogenic mechanisms and the availability of reliable models of disease have stimulated pharmacological research of potential therapies for DS. While treatments with nootropic agents such as piracetam and its analog SGS-111 have been unsuccessful in DS children (Lobaugh et al., 2001) and in DS mouse models (Moran et al., 2002, Rueda et al., 2008b), other studies targeting the main pathological mechanisms described above, i.e., oxidative stress, unbalanced synaptic

Conclusions

Reduced neuron numbers are found in cortex, hippocampus and cerebellum of DS brain and are accompanied by impaired neuronal function. Brain hypocellularity is acquired during early developmental stages and is paralleled by impaired cognitive development leading to intellectual disabilities. Further deterioration of cognitive abilities occurs in adolescence and adulthood possibly due to superimposing degenerative mechanisms. Although the syndrome invariably results in AD-like neuropathology, the

Acknowledgements

This work was supported by grants from the Fondation Jérôme Lejeune-France (to AC), Compagnia di San Paolo-Torino (to LG and FB) and Telethon-Italy (CGP09534 to FB).

References (332)

  • S. Clark et al.

    Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome

    Exp. Neurol.

    (2006)
  • L. Conti et al.

    Controlling neural stem cell division within the adult subventricular zone: an APPealing job

    Trends Neurosci.

    (2005)
  • A.C. Costa et al.

    Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome

    Neurosci. Lett.

    (2005)
  • A.C. Costa et al.

    Motor dysfunction in a mouse model for Down syndrome

    Physiol. Behav.

    (1999)
  • J.T. Coyle et al.

    Down syndrome. Alzheimer's disease and thetrisomy 16 mouse

    Trends Neurosci.

    (1988)
  • D.R. Crawford et al.

    Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress

    Arch. Biochem. Biophys.

    (1997)
  • A.J. Dalton et al.

    Clinical expression of Alzheimer's disease in Down's syndrome

    Psychiatr. Clin. North Am.

    (1986)
  • D.J. David et al.

    Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression

    Neuron

    (2009)
  • P. Davies et al.

    Selective loss of central cholinergic neurons in Alzheimer's disease

    Lancet

    (1976)
  • G.E. Demas et al.

    Spatial memory deficits in segmental trisomic Ts65Dn mice

    Behav. Brain Res.

    (1996)
  • G.E. Demas et al.

    Impaired spatial working and reference memory in segmental trisomy (Ts65Dn) mice

    Behav. Brain Res.

    (1998)
  • G. Ermak et al.

    Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease

    J. Biol. Chem.

    (2001)
  • R.M. Escorihuela et al.

    A behavioral assessment of Ts65Dn mice: a putative Down syndrome model

    Neurosci. Lett.

    (1995)
  • R.M. Escorihuela et al.

    Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome

    Neurosci. Lett.

    (1998)
  • F. Fernandez et al.

    Episodic-like memory in Ts65Dn, a mouse model of Down syndrome

    Behav. Brain Res.

    (2008)
  • J.L. Fiedler et al.

    Regional alteration of cholinergic function in central neurons of trisomy 16 mouse fetuses, an animal model of human trisomy 21 (Down syndrome)

    Brain Res.

    (1994)
  • E.C. Akeson et al.

    Ts65Dn—localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome

    Cytogenet Cell Genet.

    (2001)
  • G.E. Alexander et al.

    Relation of age and apolipoprotein E to cognitive function in Down syndrome adults

    Neuroreport

    (1997)
  • E.S. Antonarakis et al.

    The challeng of Down syndrome

    Trends Mol. Med.

    (2006)
  • S.E. Antonarakis et al.

    Chromosome 21 and Down syndrome: from genomics to pathophysiology

    Nat. Rev. Genet.

    (2004)
  • J.R. Arron et al.

    NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21

    Nature

    (2006)
  • E.H. Aylward et al.

    Cerebellar volume in adults with Down syndrome

    Arch. Neurol.

    (1997)
  • E.H. Aylward et al.

    MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia

    Am. J. Psychiatry

    (1999)
  • M.J. Ball et al.

    Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down syndrome: quantitative comparison with Alzheimer dementia

    Ann. Neurol.

    (1980)
  • S.L. Ball et al.

    Personality and behaviour changes mark the early stages of Alzheimer's disease in adults with Down's syndrome: findings from a prospective population-based study

    Int. J. Geriatr. Psychiatry

    (2006)
  • S.L. Ball et al.

    Executive dysfunction and its association with personality and behaviour changes in the development of Alzheimer's disease in adults with Down syndrome and mild to moderate learning disabilities

    Brit. J. Clin. Psychol.

    (2008)
  • L.L. Bambrick et al.

    Neuronal apoptosis in mouse trisomy 16: mediation by caspases

    J. Neurochem.

    (1999)
  • L.L. Bambrick et al.

    Altered astrocyte calcium homeostasis and proliferation in theTs65Dn mouse, a model of Down syndrome

    J. Neurosci. Res.

    (2003)
  • R.T. Bartus et al.

    The cholinergic hypothesis of geriatric memory dysfunction

    Science

    (1982)
  • L.L. Baxter et al.

    Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse

    Hum. Mol. Genet.

    (2000)
  • L.E. Becker et al.

    Dendritic atrophy in children with Down's syndrome

    Ann. Neurol.

    (1986)
  • P.N. Belichenko et al.

    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)
  • P.V. Belichenko et al.

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

    J. Comp. Neurol.

    (2009)
  • P.V. Belichenko et al.

    Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships

    J. Comp. Neurol.

    (2007)
  • P.V. Belichenko et al.

    Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome

    J. Comp. Neurol.

    (2004)
  • F. Benfenati

    Synaptic plasticity and the neurobiology of learning and memory

    Acta Biomed.

    (2007)
  • M.R. Bennett et al.

    Dynamics of the CA3 pyramidal neuron autoassociative memory network in the hippocampus

    Philos. Trans. R. Soc. Lond. B Biol. Sci.

    (1994)
  • T.K. Best et al.

    Abnormal synaptic properties in Down syndrome: lessons from mouse models

    Cell. Sci. Rev.

    (2006)
  • P. Bianchi et al.

    Lithium restores neurogenesis in the subventricular zone of the Ts65Dn mouse, a model for Down syndrome

    Brain Pathol.

    (2009)
  • A.H. Bittles et al.

    The four ages of Down syndrome

    Eur. J. Public Health

    (2006)
  • Cited by (106)

    • Number estimation in Down syndrome: Cognition or experience?

      2022, Research in Developmental Disabilities
    • Neurological and neurodevelopmental manifestations in children and adolescents with Down syndrome

      2022, International Review of Research in Developmental Disabilities
      Citation Excerpt :

      A clear pathophysiologic understanding of what drives individual variation in DS remains elusive. A prominent and nearly universal feature in DS is intellectual disability (ID), with cognitive abilities ranging from borderline abilities to profound cognitive impairment, with most individuals falling in the mild to moderate range of ID (Contestabile, Benfenati, & Gasparini, 2010; Vicari, Bellucci, & Carlesimo, 2005). IQ testing typically falls between 30 and 70, though cognitive abilities often do not develop evenly in DS.

    • Down Syndrome

      2020, Encyclopedia of Infant and Early Childhood Development
    View all citing articles on Scopus
    View full text