DS

Question 1

Individuals with DS show an array of altered cognitive and behavioural phenotypes, including the

Answer 1

incomplete and delayed acquisition of motor, linguistic and visual-spatial abilities, impairments in learning and memory, and neurobehavioral disorders with a higher risk of developing Alzheimer-like dementia by the age of 40.

Question 2

What similarities does Hsa21 have with mouse chromosomes and why is this useful for mouse models?

Answer 2

The long arm of Hsa21 contains approximately 552 genes, 166 of which are orthologous to genes localized in syntenic regions of three mouse chromosomes: Mmu16, Mmu17 and Mmu10 with 110, 19 and 37 orthologous genes, respectively. Based on these homologies, several mouse models that are trisomic for different sets of Hsa21 genes have been developed

Question 3

What does Ts65Dn contain?

Answer 3

bears a partial trisomy of a segment of Mmu16, extending from the Mrp139 to the Znf295 genes, and contains approximately 92 genes orthologous to Hsa21 genes

~10 Mb of Mmu17 containing 60 genes nonhomologous to Hsa21.

Question 4

What behavioural similarities do Ts65Dn mice have with DS phenotypes?

Answer 4

motor dysfunction (Costa et al., 1999), attention deficits (Discroll et al. 2004) and impairments in performing hippocampal-dependent tasks (for example Sago et al., 2000)

Question 5

TC1 was made by who?

Answer 5

O’Doherty, 2005

Question 6

What limits TC1?

Answer 6

variable levels of mosaicism of the extra chromosome in different tissues, limits the analysis of phenotypic consequences.

Question 7

What alterations are seen in DS neuromorphology?

Answer 7

volume of the brain and number of neurons is reduced (Guidi et al., 2008; Guidi et al.,2011)

Question 8

What do Ts65Dn mice show about the hippocampus?

Answer 8

Studies of the hippocampus in Ts65Dn mice demonstrate that these volume reductions are localized to the hippocampal granule cell layer and hilus (Bianchi, 2010).

Question 9

Where else have Ts65Dn mice been shown to have hypocellularity and during what stages?

Answer 9

during prenatal and early postnatal stages in the neocortex (Chakrabati, 2007), the CA1 and dentate gyrus of the hippocampus (Kurt, 2004) as well as in the cerebellum (Baxter, 2000)

Question 10

What do studies of the cholinergic system elude to in Ts65Dn mice?

Answer 10

Ts65Dn mice show a deficit in the cholinergic system as they age (Seo, 2005) which may explain the neurodegeration of basal forebrain structures rich in cholinergic neurons in the adult DS brain (Lott, 2012) that have been associated with cognitive decline (Granholm, 2000)

Question 11

Why might there be hypocellularity in DS individuals?

Answer 11

Studies with Ts65Dn mice indicate that these neuroanatomical alterations could be caused by impairment of cell proliferation via extension of the cell cycle during embryonic stages in CA3 and early life in the DAG (Chakrabati, 2007) as well as increased apoptosis or neurodegeneration.

Question 12

What is DYRK1A?

Answer 12

dual specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A)

codes for a serine-threonine protein kinase, that is essential for normal postembryonic neurogenesis and appears to be implicated in multiple biological pathways.

Question 13

What does overexpression of DYRK1A show in mice?

Answer 13

inhibits proliferation, induces premature differentiation of neural progenitor cells in the developing mouse cerebral cortex, and impairs G1/G0-S phase transition in rat hippocampal progenitor cells (Park, 2010)

Question 14

Ortiz-Abalia et al. 2008 found that normalization of DRYK1A expression through

Answer 14

injection of a virus mediated RNA inhibitor rescued motor alterations in mice with overexpressed DYRK1A

Question 15

Who related APP to patched 1 signalling?

Answer 15

Trazzi et al. (2011) related increased levels of the APP intracellular domain with the overexpression of patched 1, a negative regulator of the sonic hedgehog pathway, which may account for proliferation impairment

Question 16

Why might APP lead to differential differentiation?

Answer 16

APP overexpression may also alter the differentiation of stem cells by acting on the Notch pathway, which is implicated in the acquisition of a glial phenotype (Morrison, 2000).

Question 17

Where has Notch signalling been shown to be upregulated and what are the implications of this?

Answer 17

Notch is upregulated in the cortex of DS and AD patients and in DS fibroblasts (Fischer, 2005); therefore, it could shift the balance towards a glial phenotype rather than a neuronal phenotype in stem cells

Question 18

Which GABA-A antagonists have been used on TS65Dn mice and what have they shown?

Answer 18

picrotoxin, bilobalide, or pentylenetetrazole restored LTP and cognition in the object recognition test in these mice (Fernandez, 2007)

Question 19

What selective GABA-A inverse agonist was used and what did this rescue in TS65Dn mice?

Answer 19

RG1662 was shown to rescue learning and memory deficits in Ts65Dn mice (Martínez-Cué, 2013)

Phase II ineffective

Question 20

Why would memenatine help with reductions in LTP?

Answer 20

memantine, a partial agonist of NMDAR, rescued several DS-relevant phenotypes in TS65Dn mice presumably through inhibiting low frequency activation of NMDAR’s that prevents LTP (Coan,1989); this has been shown in conditions of low extracellular Mg2+ (Frankiewics and Parsons, 1999) where memantine may act as a surrogate for Mg2+, restoring coincidence detection of NMDAR’s (Rommes, 2008)

Question 21

What has memantine shown in adult individuals with DS?

Answer 21

Despite showing efficicacy in AD patients and Ts65Dn mice, clinical trials of memantine failed to demonstrate any benefit on cognitive impairment and dementia in adult DS patients (Hanney et al., 2012)

Question 22

Who showed that fluoxetine rescues DS phenotypes in mice when administered prenatally?

Answer 22

Bianchi, 2010; Stagni, 2013

Question 23

Who showed that fluoxetine was ineffective when administered postnatally and on what?

Answer 23

ineffective both in TS65Dn mice (Heinen et al.,2012) and adolescent patients (Fatima et al., 1998) when administered postnatally

Question 24

What supplement has been given prenatally to mothers that has shown improvement in DS-relevant phentoypes?

Answer 24

This was found to be the case in drugs that target the cholinergic system where ACEI’s administered in post-natal mice and humans have been largely ineffective but maternal choline supplements have been found to improve spatial memory in Ts65Dn mice (Velazquez, 2013).