Synaptic and cognitive abnormalities in mouse models of down syndrome: Exploring genotype‐phenotype relationships

Belichenko, Pavel V.; Kleschevnikov, Alexander M.; Salehi, Ahmad; Epstein, Charles J.; Mobley, William C.

doi:10.1002/cne.21433

Cited by 187 publications

(190 citation statements)

References 82 publications

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“…However, the Ts1Cje mouse shows spine and connectivity alterations (60) and reduction in cerebellar granule cell number (61) less severe than the Ts65Dn mouse. Interestingly a high resolution analysis of human segmental trisomies suggests that more than one mental retardation critical region of HSA21 exists (62).…”

Section: The App/aicd-dependent Alteration Of the Shh Pathway Impairsmentioning

confidence: 99%

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

Trazzi¹,

Fuchs²,

Valli

et al. 2013

Journal of Biological Chemistry

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Background: Individuals with Down syndrome suffer from mental retardation due to severe neurogenesis impairment. Results: Normalization of the triplicated gene APP expression restores neuronal maturation and differentiation in trisomic neuronal precursors. Conclusion: APP overproduction contributes to neurogenesis impairment in DS.Significance: APP signaling may be a target for therapeutic approaches aiming to improve brain development in DS.

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Section: The App/aicd-dependent Alteration Of the Shh Pathway Impairsmentioning

confidence: 99%

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

Trazzi¹,

Fuchs²,

Valli

et al. 2013

Journal of Biological Chemistry

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“…Previous studies have pointed a higher level of inhibition in some regions of the neocortex and the hippocampus (Belichenko et al 2004(Belichenko et al , 2007(Belichenko et al , 2009Kurt et al 2000). In this sense, treatment with picrotoxin (a GABA A receptor antagonist), improves behavioural performance (Fernandez et al 2007).…”

Section: Discussionmentioning

confidence: 95%

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

et al. 2010

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Down's syndrome (DS), with an incidence of one in 800 live births, is the most common genetic disorder associated with mental retardation. This trisomy on chromosome 21 induces a variable phenotype in which the only common feature is the presence of mental retardation. The neural mechanisms underlying mental retardation might include defects in the formation of neuronal networks and neural plasticity. DS patients have alterations in the morphology, the density and the distribution of dendritic spines in the pyramidal neurons of the cortex. Our hypothesis is that the deficits in dendritic arborization observed in the principal neurons of DS patients and Ts65Dn mice (a model for DS that mimics most of the structural alterations observed in humans) may be mediated to some extent by changes in their inhibitory inputs. Different types of interneurons control different types of inhibition. Therefore, to understand well the changes in inhibition in DS, it is necessary to study the different types of interneurons separately. We have studied the expression of synaptophysin, Glutamic acid decarboxylase-67 (GAD-67) and calcium-binding protein-expressing cells in the primary somatosensory cortex of 4-5 month old Ts65Dn mice. We have observed an increment of GAD67 immunoreactivity that is related mainly to an increment of calretinin-immunoreactive cells and among them the ones with bipolar morphology. Since there is a propensity for epilepsy in DS patients, this increase in interneurons might reflect an attempt by the system to block overexcitation rather than an increment in total inhibition and could explain the deficit in interneurons and principal cells observed in elderly DS patients.

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“…The most widely used DS mouse model, Ts65Dn mice, are trisomic for more than half of the mouse orthologs of genes on human chromosome 21 (59), whereas Ts1Cje mice carry a smaller segmental triplication included in Ts65Dn trisomy (60). That these two models display DS-characteristic growth retardation suggests that certain genes within the triplicated region are responsible, at least in part, for the phenotype (45,46,61). DYRK1A transgenic (Tg) mouse models were also made in an effort to reveal its role in DS.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Xiang

Ning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1. Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level. Transgenic DS mice overexpressing DYRK1A showed reduced Hap1-Dcaf7 association in the hypothalamus. Furthermore, the overexpression of DYRK1A in the hypothalamus led to delayed growth in postnatal mice, suggesting that DYRK1A regulates the Hap1-Dcaf7 interaction and postnatal growth and that targeting Hap1 or Dcaf7 could ameliorate growth retardation in DS.H untingtin-associated protein 1 (Hap1) is a cytoplasmic protein highly expressed in neurons of the CNS (1, 2). Hap1 was initially recognized for its binding to polyglutamine-expanded huntingtin (Htt), the protein responsible for Huntington's disease (3). Because Hap1 is expressed at various levels in different types of neurons (1,(4)(5)(6)(7)(8), it is likely involved in cell type-specific functions of the brain. For example, Hap1 is abundantly expressed in the hypothalamus, and its expression in the hypothalamus influences the central control of feeding (9); as a direct result, mice lacking Hap1 are malnourished and die in the early postnatal period (5, 10, 11). The function of Hap1 is also age dependent and appears to be important for postnatal neurogenesis in the paraventricular nuclei, the lateral hypothalamus (5, 11), and the dentate gyrus of the hippocampus (7).The specific function of Hap1 in the hypothalamus may be associated with unique cytoplasmic structures called "stigmoid bodies" (SBs), which are formed by Hap1 in the hypothalamus (12, 13) and appear to be non-membrane-bound, ovoid to circular in shape, and 0.5-3 μm in diameter (14,15). Widely regarded as a determinant marker for SBs, Hap1 is capable of sequestering several important disease-related proteins into SB-like inclusions in cell cultures, including Abelson helper integration site 1 (Ahi1), androgen receptor, TBP, and ataxin-3 (6, 16-18). However, in vivo evidence for such sequestration exists only for Ahi1, which is responsible for specific forms of Joubert syndrome. Other proteins, such as SorLA/LR11, sortilin, 5-HT 7 receptor, and 14-3-3, are also reported to be associated with . Although SBs are abundant in the hypothalamus, their functions remain elusive, despite speculation that they might be involved in sex-steroid maturation (15). We bel...

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Synaptic and cognitive abnormalities in mouse models of down syndrome: Exploring genotype‐phenotype relationships

Cited by 187 publications

References 82 publications

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

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