Multi-influential Genetic Interactions Alter Behaviour and Cognition Through Six Main Biological Cascades in Down Syndrome Mouse Models

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2021 Mar 11

PMID 33693642

Citations 19

Authors

Arnaud Duchon

Maria Del Mar Muniz Moreno

Sandra Martin Lorenzo

Marcia Priscilla Silva de Souza

Claire Chevalier

Valerie Nalesso

Hamid Meziane

Paulo Loureiro de Sousa

Vincent Noblet

Jean-Paul Armspach

Veronique Brault

Yann Herault

Affiliations

Soon will be listed here.

Abstract

Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype-phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 16 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted six biological cascades centred around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.

Citing Articles

Infantile Spasms in Pediatric Down Syndrome: Potential Mechanisms Driving Therapeutic Considerations.

Stafstrom C, Shao L Children (Basel). 2025; 11(12.

PMID: 39767942 PMC: 11674231. DOI: 10.3390/children11121513.

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model.

Llambrich S, Tielemans B, Salien E, Atzori M, Wouters K, Van Bulck V Elife. 2024; 12.

PMID: 38497812 PMC: 10948151. DOI: 10.7554/eLife.89763.

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome.

Serrano M, Kim E, Siow B, Ma D, Rojo L, Simmons C Neurobiol Dis. 2024; 188:106336.

PMID: 38317803 PMC: 7615598. DOI: 10.1016/j.nbd.2023.106336.

Volume of the thalamus and hypothalamus in the Ts1Rhr and Ms1Rhr mouse models relevant to Down syndrome.

Arthun J, Aldaz S, Hayes P, Roberts J, Olson L MicroPubl Biol. 2023; 2023.

PMID: 38021171 PMC: 10644112. DOI: 10.17912/micropub.biology.000981.

Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model.

Hawley L, Stringer M, Deal A, Folz A, Goodlett C, Roper R Neurobiol Dis. 2023; 190:106359.

PMID: 37992782 PMC: 10843801. DOI: 10.1016/j.nbd.2023.106359.

References

Reeves R, Irving N, Moran T, WOHN A, Kitt C, Sisodia S . A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995; 11(2):177-84. DOI: 10.1038/ng1095-177. View

Ung D, Iacono G, Meziane H, Blanchard E, Papon M, Selten M . Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse. Mol Psychiatry. 2017; 23(5):1356-1367. PMC: 5984103. DOI: 10.1038/mp.2017.39. View

Belichenko P, Kleschevnikov A, Salehi A, Epstein C, Mobley W . Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol. 2007; 504(4):329-45. DOI: 10.1002/cne.21433. View

Belichenko N, Belichenko P, Kleschevnikov A, Salehi A, Reeves R, Mobley W . 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; 29(18):5938-48. PMC: 3849469. DOI: 10.1523/JNEUROSCI.1547-09.2009. View

McCormick M, Schinzel A, Petersen M, Stetten G, Driscoll D, Cantu E . Molecular genetic approach to the characterization of the "Down syndrome region" of chromosome 21. Genomics. 1989; 5(2):325-31. DOI: 10.1016/0888-7543(89)90065-7. View

King M, Pardo M, Cheng Y, Downey K, Jope R, Beurel E . Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments. Pharmacol Ther. 2013; 141(1):1-12. PMC: 3867580. DOI: 10.1016/j.pharmthera.2013.07.010. View

Herault Y, Duchon A, Velot E, Marechal D, Brault V . The in vivo Down syndrome genomic library in mouse. Prog Brain Res. 2012; 197:169-97. DOI: 10.1016/B978-0-444-54299-1.00009-1. View

Xu R, Brawner A, Li S, Liu J, Kim H, Xue H . OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome. Cell Stem Cell. 2019; 24(6):908-926.e8. PMC: 6944064. DOI: 10.1016/j.stem.2019.04.014. View

Escorihuela R, Fernandez-Teruel A, Vallina I, Baamonde C, Lumbreras M, Dierssen M . A behavioral assessment of Ts65Dn mice: a putative Down syndrome model. Neurosci Lett. 1995; 199(2):143-6. DOI: 10.1016/0304-3940(95)12052-6. View

10.

Mao R, Zielke C, Zielke H, Pevsner J . Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics. 2003; 81(5):457-67. DOI: 10.1016/s0888-7543(03)00035-1. View

11.

Desai A, Razeghin M, Meruvia-Pastor O, Pena-Castillo L . GeNET: a web application to explore and share Gene Co-expression Network Analysis data. PeerJ. 2017; 5:e3678. PMC: 5560228. DOI: 10.7717/peerj.3678. View

12.

Antonarakis S . Down syndrome and the complexity of genome dosage imbalance. Nat Rev Genet. 2016; 18(3):147-163. DOI: 10.1038/nrg.2016.154. View

13.

Korenberg J . Molecular mapping of the Down syndrome phenotype. Prog Clin Biol Res. 1990; 360:105-15. View

14.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

15.

Guedj F, Lopes Pereira P, Najas S, Barallobre M, Chabert C, Souchet B . DYRK1A: a master regulatory protein controlling brain growth. Neurobiol Dis. 2012; 46(1):190-203. DOI: 10.1016/j.nbd.2012.01.007. View

16.

Lyle R, Bena F, Gagos S, Gehrig C, Lopez G, Schinzel A . Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur J Hum Genet. 2008; 17(4):454-66. PMC: 2986205. DOI: 10.1038/ejhg.2008.214. View

17.

de la Torre R, de Sola S, Hernandez G, Farre M, Pujol J, Rodriguez J . Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016; 15(8):801-810. DOI: 10.1016/S1474-4422(16)30034-5. View

18.

Rahmani Z, Blouin J, Watkins P, Mattei J, POISSONNIER M, PRIEUR M . Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome. Proc Natl Acad Sci U S A. 1989; 86(15):5958-62. PMC: 297750. DOI: 10.1073/pnas.86.15.5958. View

19.

Seo H, Isacson O . Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice. Exp Neurol. 2005; 193(2):469-80. DOI: 10.1016/j.expneurol.2004.11.017. View

20.

Duchon A, Herault Y . DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome. Front Behav Neurosci. 2016; 10:104. PMC: 4891327. DOI: 10.3389/fnbeh.2016.00104. View