Down syndrome: the brain in trisomic mode

KEY POINTS * Down syndrome results from the presence of an extra copy or major portion of human chromosome 21 (_Homo sapiens_ autosome 21 (HSA21)), producing a genetic imbalance. * Our

understanding of Down syndrome has shifted from a causative gene-based view to one in which genes, deregulation of non-coding elements and epigenetic factors influence the disease phenotype.

* In Down syndrome, the ability to keep incoming information online, the performance of mental computations on such information and the storage of this information for future use are

disrupted. * The size of certain brain regions affected in Down syndrome is correlated with performance in tests of intelligence and language. * HSA21-encoded proteins with master regulator

functions, such as transcription or splicing efficiency of specific mRNA, may exert a combinatorial effect by promoting or inhibiting the transcription or splicing of their targets, thus

spreading the effect of trisomy 21 to genes outside HSA21. * Many strategies have been used to model Down syndrome in mice. Mouse trisomies allow analysis of Down syndrome neurobiology, the

importance of specific chromosomal regions and understanding the efficacy of treatments. Single-gene transgenesis is a complementary approach in which we may better dissect the gene-specific

effects of recapitulated Down syndrome phenotypes. * In the past few years, we have made notable advances in finding a 'cure' for Down syndrome-linked intellectual disability

based on symptomatic alleviation and individual gene function rescue. ABSTRACT Down syndrome is the most common form of intellectual disability and results from one of the most complex

genetic perturbations that is compatible with survival, trisomy 21. The study of brain dysfunction in this disorder has largely been based on a gene discovery approach, but we are now moving

into an era of functional genome exploration, in which the effects of individual genes are being studied alongside the effects of deregulated non-coding genetic elements and epigenetic

influences. Also, new data from functional neuroimaging studies are challenging our views of the cognitive phenotypes associated with Down syndrome and their pathophysiological correlates.

These advances hold promise for the development of treatments for intellectual disability. Access through your institution Buy or subscribe This is a preview of subscription content, access

via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $189.00 per year only $15.75 per issue Learn more Buy

this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: *

Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CONSEQUENCES OF TRISOMY 21 FOR BRAIN DEVELOPMENT IN DOWN

SYNDROME Article 08 October 2024 THE CONTRIBUTION OF COPY NUMBER VARIANTS TO PSYCHIATRIC SYMPTOMS AND COGNITIVE ABILITY Article 03 February 2023 _ELP2_ MUTATIONS PERTURB THE EPITRANSCRIPTOME

AND LEAD TO A COMPLEX NEURODEVELOPMENTAL PHENOTYPE Article Open access 11 May 2021 REFERENCES * Megarbane, A. et al. The 50th anniversary of the discovery of trisomy 21: the past, present,

and future of research and treatment of Down syndrome. _Genet. Med._ 11, 611–616 (2009). Article  PubMed  Google Scholar  * Lott, I. T. & Dierssen, M. Cognitive deficits and associated

neurological complications in individuals with Down's syndrome. _Lancet Neurol._ 9, 623–633 (2010). Article  PubMed  Google Scholar  * Khoshnood, B., Greenlees, R., Loane, M. &

Dolk, H. Paper 2: EUROCAT public health indicators for congenital anomalies in Europe. _Birth Defects Res. A Clin. Mol. Teratol._ 91, S16–S22 (2011). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Parker, S. E. et al. Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004–2006. _Birth Defects Res. A Clin. Mol. Teratol._ 88,

1008–1016 (2010). Article  CAS  PubMed  Google Scholar  * Hattori, M. et al. The DNA sequence of human chromosome 21. _Nature_ 405, 311–319 (2000). A STUDY THAT REVEALED THE SEQUENCE AND

GENE CATALOGUE OF THE LONG ARM OF CHROMOSOME 21, WHICH WERE CRUCIAL FINDINGS FOR DOWN SYNDROME RESEARCH. Article  CAS  PubMed  Google Scholar  * Lott, I. T. Neurological phenotypes for Down

syndrome across the life span. _Prog. Brain Res._ 197, 101–121 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Vicari, S., Bellucci, S. & Carlesimo, G. A. Visual and

spatial long-term memory: differential pattern of impairments in Williams and Down syndromes. _Dev. Med. Child Neurol._ 47, 305–311 (2005). A PAPER DETAILING THE DIFFERENCES IN THE COGNITIVE

PROFILES IN DOWN AND WILLIAMS SYNDROMES, WHICH HAVE HELPED TO GAIN INSIGHT INTO THE HIPPOCAMPAL FUNCTION AND THE STRUCTURE–FUNCTION RELATIONSHIP IN INTELLECTUAL DISABILITY. Article  PubMed

  Google Scholar  * Conners, F. A., Moore, M. S., Loveall, S. J. & Merrill, E. C. Memory profiles of Down, Williams, and fragile X syndromes: implications for reading development. _J.

Dev. Behav. Pediatr._ 32, 405–417 (2011). Article  PubMed  Google Scholar  * Edgin, J. O., Pennington, B. F. & Mervis, C. B. Neuropsychological components of intellectual disability: the

contributions of immediate, working, and associative memory. _J. Intellect. Disabil. Res._ 54, 406–417 (2010). Article  PubMed  PubMed Central  Google Scholar  * Baddeley, A. & Jarrold,

C. Working memory and Down syndrome. _J. Intellect. Disabil. Res._ 51, 925–931 (2007). BADDELEY PROPOSED THAT WORKING MEMORY COULD BE DIVIDED INTO THREE SUBSYSTEMS: ONE THAT IS CONCERNED

WITH VERBAL AND ACOUSTIC INFORMATION (THE PHONOLOGICAL LOOP); A SECOND THAT IS CONCERNED WITH THE VISUOSPATIAL SKETCHPAD; AND A THIRD THAT IS AN ATTENTIONALLY LIMITED CONTROL SYSTEM (THE

CENTRAL EXECUTIVE), ON WHICH THE FIRST AND SECOND ARE DEPENDENT. A FOURTH SUBSYSTEM, THE EPISODIC BUFFER, HAS NOW BEEN ADDED TO THIS OPERATIONAL MODEL. Article  CAS  PubMed  Google Scholar 

* Lanfranchi, S., Baddeley, A., Gathercole, S. & Vianello, R. Working memory in Down syndrome: is there a dual task deficit? _J. Intellect. Disabil. Res._ 56, 157–166 (2011). Article 

PubMed  Google Scholar  * Dierssen, M., Herault, Y. & Estivill, X. Aneuploidy: from a physiological mechanism of variance to Down syndrome. _Physiol. Rev._ 89, 887–920 (2009). Article 

CAS  PubMed  Google Scholar  * Chapman, R. S. & Hesketh, L. J. Behavioral phenotype of individuals with Down syndrome. _Ment. Retard. Dev. Disabil. Res. Rev._ 6, 84–95 (2000). Article 

CAS  PubMed  Google Scholar  * Laws, G. & Bishop, D. V. A comparison of language abilities in adolescents with Down syndrome and children with specific language impairment. _J. Speech

Lang. Hear. Res._ 46, 1324–1339 (2003). Article  PubMed  Google Scholar  * Purser, H. R. M. & Jarrold, C. Impaired verbal short-term memory in Down syndrome reflects a capacity

limitation rather than atypically rapid forgetting. _J. Exp. Child Psychol._ 91, 1–23 (2005). Article  Google Scholar  * Zimmer, H. D. Visual and spatial working memory: from boxes to

networks. _Neurosci. Biobehav. Rev._ 32, 1373–1395 (2008). Article  PubMed  Google Scholar  * Visu-Petra, L., Benga, O., Tincas, I. & Miclea, M. Visual-spatial processing in children and

adolescents with Down's syndrome: a computerized assessment of memory skills. _J. Intellect. Disabil. Res._ 51, 942–952 (2007). Article  CAS  PubMed  Google Scholar  * Lanfranchi, S.,

Carretti, B., Spano, G. & Cornoldi, C. A specific deficit in visuospatial simultaneous working memory in Down syndrome. _J. Intellect. Disabil. Res._ 53, 474–483 (2009). Article  CAS 

PubMed  Google Scholar  * Colom, R., Jung, R. E. & Haier, R. J. General intelligence and memory span: evidence for a common neuroanatomic framework. _Cogn. Neuropsychol._ 24, 867–878

(2007). Article  PubMed  Google Scholar  * Jarrold, C. & Towse, J. N. Individual differences in working memory. _Neuroscience_ 139, 39–50 (2006). Article  CAS  PubMed  Google Scholar  *

Nairne, J. S. Remembering over the short-term: the case against the standard model. _Annu. Rev. Psychol._ 53, 53–81 (2002). Article  PubMed  Google Scholar  * Nash, H. & Heath, J. The

role of vocabulary, working memory and inference making ability in reading comprehension in Down syndrome. _Res. Dev. Disabil._ 32, 1782–1791 (2011). Article  PubMed  Google Scholar  *

Saito, S., Jarrold, C. & Riby, D. M. Exploring the forgetting mechanisms in working memory: evidence from a reasoning span test. _Q. J. Exp. Psychol._ 62, 1401–1419 (2009). Article 

Google Scholar  * Lanfranchi, S., Jerman, O., Dal Pont, E., Alberti, A. & Vianello, R. Executive function in adolescents with Down Syndrome. _J. Intellect. Disabil. Res._ 54, 308–319

(2010). Article  CAS  PubMed  Google Scholar  * Lemons, C. J. & Fuchs, D. Phonological awareness of children with Down syndrome: its role in learning to read and the effectiveness of

related interventions. _Res. Dev. Disabil._ 31, 316–330 (2010). Article  PubMed  Google Scholar  * Jarrold, C., Cocksey, J. & Dockerill, E. Phonological similarity and lexicality effects

in children's verbal short-term memory: concerns about the interpretation of probed recall data. _Q. J. Exp. Psychol._ 61, 324–340 (2008). Article  Google Scholar  * Fidler, D. J.,

Most, D. E. & Guiberson, M. M. Neuropsychological correlates of word identification in Down syndrome. _Res. Dev. Disabil._ 26, 487–501 (2005). Article  PubMed  Google Scholar  * Jarrold,

C., Baddeley, A. D. & Phillips, C. E. Verbal short-term memory in Down syndrome: a problem of memory, audition, or speech? _J. Speech Lang. Hear. Res._ 45, 531–544 (2002). Article 

PubMed  Google Scholar  * Brock, J. & Jarrold, C. Serial order reconstruction in Down syndrome: evidence for a selective deficit in verbal short-term memory. _J. Child Psychol.

Psychiatry_ 46, 304–316 (2005). Article  PubMed  Google Scholar  * Robertson Ringenbach, S. D., Chua, R., Maraj, B. K., Kao, J. C. & Weeks, D. J. Bimanual coordination dynamics in adults

with Down syndrome. _Motor Control_ 6, 388–407 (2002). Article  PubMed  Google Scholar  * Robertson, S. D., Van Gemmert, A. W. & Maraj, B. K. Auditory information is beneficial for

adults with Down syndrome in a continuous bimanual task. _Acta Psychol._ 110, 213–229 (2002). Article  Google Scholar  * Elliott, D., Weeks, D. J. & Gray, S. Manual and oral praxis in

adults with Down's syndrome. _Neuropsychologia_ 28, 1307–1315 (1990). Article  CAS  PubMed  Google Scholar  * Elliott, D. & Weeks, D. J. Cerebral specialization and the control of

oral and limb movements for individuals with Down's syndrome. _J. Mot Behav._ 22, 6–18 (1990). Article  CAS  PubMed  Google Scholar  * Welsh, T. N. & Elliott, D. Gender differences

in a dichotic listening and movement task: lateralization or strategy? _Neuropsychologia_ 39, 25–35 (2001). Article  CAS  PubMed  Google Scholar  * Brunamonti, E. et al. Cognitive control of

movement in Down syndrome. _Res. Dev. Disabil._ 32, 1792–1797 (2011). Article  PubMed  Google Scholar  * Davis, W. E. & Kelso, J. A. Analysis of “invariant characteristics” in the motor

control of down's syndrome and normal subjects. _J. Mot. Behav._ 14, 194–212 (1982). Article  CAS  PubMed  Google Scholar  * Virji-Babul, N. et al. Altered brain dynamics during

voluntary movement in individuals with Down syndrome. _Neuroreport_ 22, 358–364 (2011). Article  PubMed  Google Scholar  * Vicari, S., Bellucci, S. & Carlesimo, G. A. Implicit and

explicit memory: a functional dissociation in persons with Down syndrome. _Neuropsychologia_ 38, 240–251 (2000). Article  CAS  PubMed  Google Scholar  * Vakil, E. & Lifshitz-Zehavi, H.

Solving the Raven Progressive Matrices by adults with intellectual disability with/without Down syndrome: different cognitive patterns as indicated by eye-movements. _Res. Dev. Disabil._ 33,

645–654 (2012). Article  PubMed  Google Scholar  * Pinter, J. D., Eliez, S., Schmitt, J. E., Capone, G. T. & Reiss, A. L. Neuroanatomy of Down's syndrome: a high-resolution MRI

study. _Am. J. Psychiatry_ 158, 1659–1665 (2001). A SEMINAL PAPER SHOWING THE ALTERED NEUROANATOMY IN PATIENTS WITH DOWN SYNDROME PATIENTS USING MRI. Article  CAS  PubMed  Google Scholar  *

Raz, N. et al. Selective neuroanatomic abnormalities in Down's syndrome and their cognitive correlates: evidence from MRI morphometry. _Neurology_ 45, 356–366 (1995). Article  CAS 

PubMed  Google Scholar  * Menghini, D., Costanzo, F. & Vicari, S. Relationship between brain and cognitive processes in Down syndrome. _Behav. Genet._ 41, 381–393 (2011). THIS WAS ONE OF

SEVERAL STUDIES THAT ATTEMPTED TO CORRELATE STRUCTURAL ABNORMALITIES WITH COGNITIVE EFFICIENCY. Article  PubMed  Google Scholar  * Jernigan, T. L., Bellugi, U., Sowell, E., Doherty, S.

& Hesselink, J. R. Cerebral morphologic distinctions between Williams and Down syndromes. _Arch. Neurol._ 50, 186–191 (1993). Article  CAS  PubMed  Google Scholar  * Jarrold, C.,

Baddeley, A. D. & Phillips, C. Long-term memory for verbal and visual information in Down syndrome and Williams syndrome: performance on the Doors and People test. _Cortex_ 43, 233–247

(2007). Article  PubMed  Google Scholar  * Vicari, S., Bellucci, S. & Carlesimo, G. A. Evidence from two genetic syndromes for the independence of spatial and visual working memory.

_Dev. Med. Child Neurol._ 48, 126–131 (2006). Article  PubMed  Google Scholar  * Di Filippo, M. et al. Impaired plasticity at specific subset of striatal synapses in the Ts65Dn mouse model

of Down syndrome. _Biol. Psychiatry_ 67, 666–671 (2010). Article  CAS  PubMed  Google Scholar  * Tomporowski, P. D., Hayden, A. M. & Applegate, B. Effects of background event rate on

sustained attention of mentally retarded and nonretarded adults. _Am. J. Ment. Retard._ 94, 499–508 (1990). CAS  PubMed  Google Scholar  * Rigoldi, C. et al. Gait analysis and cerebral

volumes in Down's syndrome. _Funct. Neurol._ 24, 147–152 (2009). CAS  PubMed  Google Scholar  * Jacola, L. M. et al. Functional magnetic resonance imaging of cognitive processing in

young adults with Down syndrome. _Am. J. Intellect. Dev. Disabil._ 116, 344–359 (2011). Article  PubMed  Google Scholar  * Colom, R., Karama, S., Jung, R. E. & Haier, R. J. Human

intelligence and brain networks. _Dialogues Clin. Neurosci._ 12, 489–501 (2010). PubMed  PubMed Central  Google Scholar  * Fabbro, F., Libera, L. & Tavano, A. A callosal transfer deficit

in children with developmental language disorder. _Neuropsychologia_ 40, 1541–1546 (2002). Article  PubMed  Google Scholar  * Pennington, B. F., Moon, J., Edgin, J., Stedron, J. &

Nadel, L. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. _Child Dev._ 74, 75–93 (2003). A SEMINAL PAPER SHOWING HIPPOCAMPAL DYSFUNCTION IN PATIENTS WITH DOWN

SYNDROME THAT WAS REVEALED USING SPECIFIC NEUROPSYCHOLOGICAL TESTS THAT WERE BASED ON MOUSE WORK. Article  PubMed  Google Scholar  * Sturgeon, X. & Gardiner, K. J. Transcript catalogs of

human chromosome 21 and orthologous chimpanzee and mouse regions. _Mamm. Genome_ 22, 261–271 (2011). Article  PubMed  Google Scholar  * Delabar, J. M. et al. Molecular mapping of

twenty-four features of Down syndrome on chromosome 21. _Eur. J. Hum. Genet._ 1, 114–124 (1993). Article  CAS  PubMed  Google Scholar  * Korenberg, J. R. et al. Down syndrome phenotypes: the

consequences of chromosomal imbalance. _Proc. Natl Acad. Sci. USA_ 91, 4997–5001 (1994). Article  CAS  PubMed  PubMed Central  Google Scholar  * Korbel, J. O. et al. The genetic

architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. _Proc. Natl Acad. Sci. USA_ 106, 12031–12036 (2009). THIS STUDY SHOWS THAT

DIFFERENT REGIONS OF HSA21 CONTRIBUTE TO DIFFERENT DISEASE-RELATED PHENOTYPES, ARGUING AGAINST A SINGLE CRITICAL REGION IN HSA21 (ALSO SEE REFERENCE 57). Article  PubMed  PubMed Central 

Google Scholar  * Lyle, R. et al. 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._ 17, 454–466 (2009). Article  CAS  PubMed  Google Scholar  * Dierssen, M. et al. Functional genomics of Down syndrome: a multidisciplinary approach. _J. Neural Transm. Suppl._ 61,

131–148 (2001). Google Scholar  * Pritchard, M., Reeves, R. H., Dierssen, M., Patterson, D. & Gardiner, K. J. Down syndrome and the genes of human chromosome 21: current knowledge and

future potentials. Report on the Expert workshop on the biology of chromosome 21 genes: towards gene-phenotype correlations in Down syndrome. Washington D.C., September 28-October 1, 2007.

_Cytogenet. Genome Res._ 121, 67–77 (2008). Article  CAS  PubMed  Google Scholar  * Pritchard, M. A. & Kola, I. The “gene dosage effect” hypothesis versus the “amplified developmental

instability” hypothesis in Down syndrome. _J. Neural Transm. Suppl._ 57, 293–303 (1999). CAS  PubMed  Google Scholar  * Wiseman, F. K., Alford, K. A., Tybulewicz, V. L. & Fisher, E. M.

Down syndrome—recent progress and future prospects. _Hum. Mol. Genet._ 18, R75–R83 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Toiber, D. et al. Engineering _DYRK1A_

overdosage yields Down syndrome-characteristic cortical splicing aberrations. _Neurobiol. Dis._ 40, 348–359 (2010). THIS STUDY SHOWS THAT A DOWN SYNDROME CANDIDATE GENE ON HSA21, _DYRK1A_ ,

HAS MASTER REGULATORY FUNCTIONS IN TRANSCRIPTION AND MRNA SPLICING AND THUS MAY EXERT WIDE-RANGING EFFECTS, ACTING ON GENES THAT ARE FOUND ON HSA21 AND OTHER CHROMOSOMES. ALSO SEE REFERENCES

63–65. Article  CAS  PubMed  Google Scholar  * Kahlem, P. et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. _Genome

Res._ 14, 1258–1267 (2004). THIS STUDY TESTED THE HYPOTHESIS THAT HSA21 TRANSCRIPTS ARE OVEREXPRESSED BY ABOUT 50% IN TRISOMIC CELLS. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Arron, J. R. et al. NFAT dysregulation by increased dosage of _DSCR1_ and _DYRK1A_ on chromosome 21. _Nature_ 441, 595–600 (2006). DYRK1A PHOSPHORYLATES NFAT WHILE CALCIPRESSIN 1

PHOSPHORYLATION AT THR192 BY DYRK1A ENHANCES THE ABILITY OF CALCIPRESSIN 1 TO INHIBIT THE PHOSPHATASE ACTIVITY OF CALCINEURIN, LEADING TO REDUCED NFAT TRANSCRIPTIONAL ACTIVITY. Article  CAS

  PubMed  Google Scholar  * Vilardell, M. et al. Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes. _BMC

Genomics_ 12, 229 (2011). Article  PubMed  PubMed Central  Google Scholar  * Ferrando-Miguel, R., Cheon, M. S., Yang, J. W. & Lubec, G. Overexpression of transcription factor BACH1 in

fetal Down syndrome brain. _J. Neural Transm. Suppl._ 67, 193–205 (2003). Article  CAS  Google Scholar  * Shim, K. S., Ferrando-Miguel, R. & Lubec, G. Aberrant protein expression of

transcription factors BACH1 and ERG, both encoded on chromosome 21, in brains of patients with Down syndrome and Alzheimer's disease. _J. Neural Transm. Suppl._ 67, 39–49 (2003).

Article  CAS  Google Scholar  * Osato, M. & Ito, Y. Increased dosage of the _RUNX1/AML1_ gene: a third mode of RUNX leukemia? _Crit. Rev. Eukaryot. Gene Expr._ 15, 217–228 (2005).

Article  CAS  PubMed  Google Scholar  * Altafaj, X. et al. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine

model of Down's syndrome. _Hum. Mol. Genet._ 10, 1915–1923 (2001). _DYRK1A_ IS A MAJOR CANDIDATE GENE FOR DOWN SYNDROME. THIS PAPER REPORTS THE CONSTRUCTION OF THE FIRST TRANSGENIC

MOUSE MODEL OVEREXPRESSING THIS KINASE. MANY OTHER DYRK1A OVEREXPRESSION MODELS HAVE SUBSEQUENTLY BEEN CREATED. Article  CAS  PubMed  Google Scholar  * Ahn, K. J. et al. DYRK1A BAC

transgenic mice show altered synaptic plasticity with learning and memory defects. _Neurobiol. Dis._ 22, 463–472 (2006). Article  CAS  PubMed  Google Scholar  * Ferrer, I. et al.

Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models. _Neurobiol. Dis._ 20, 392–400 (2005). THIS WAS ONE OF THE FIRST

PAPERS SUGGESTING A ROLE FOR DYRK1A IN ALZHEIMER'S DISEASE. Article  CAS  PubMed  Google Scholar  * Fuentes, J. J. et al. A new human gene from the Down syndrome critical region encodes

a proline-rich protein highly expressed in fetal brain and heart. _Hum. Mol. Genet._ 4, 1935–1944 (1995). Article  CAS  PubMed  Google Scholar  * Shapiro, B. L. Amplified developmental

instability in Down's syndrome. _Ann. Hum. Genet._ 38, 429–437 (1975). THE AMPLIFIED DEVELOPMENTAL INSTABILITY HYPOTHESIS, WHICH IS PROPOSED IN THIS PAPER, STATES THAT THE DOSAGE

IMBALANCE OF HSA21 LEADS TO A NON-SPECIFIC DISTURBANCE OF CELLULAR HOMEOSTASIS. Article  CAS  PubMed  Google Scholar  * Shapiro, B. L. Developmental instability of the cerebellum and its

relevance to Down syndrome. _J. Neural Transm. Suppl._ 61, 11–34 (2001). Google Scholar  * Olson, L. E. et al. Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable

severity of cerebellar phenotypes. _Dev. Dyn._ 230, 581–589 (2004). THIS PAPER MADE AN IMPORTANT CONTRIBUTION TO THE UNDERSTANDING OF DOWN SYNDROME CEREBELLAR PHENOTYPES. THE CEREBELLAR

ALTERATIONS IN DOWN SYNDROME WERE THOUGHT TO PARTICIPATE MAINLY IN MOTOR PHENOTYPES, BUT ABNORMALITIES IN THIS REGION ARE NOW THOUGHT TO ALSO AFFECT COGNITIVE PROCESSES. Article  CAS  PubMed

  Google Scholar  * Yu, T. et al. Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice.

_Brain Res._ 1366, 162–171 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kuhn, D. E. et al. Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and

hearts. _Biochem. Biophys. Res. Commun._ 370, 473–477 (2008). THIS STUDY SHOWED THAT HSA21-DERIVED MICRORNAS ARE OVEREXPRESSED IN DOWN SYNDROME BRAIN AND HEART SPECIMENS, LEADING TO

IMPROPER REPRESSION OF SPECIFIC TARGET PROTEINS THAT ARE LINKED TO SPECIFIC PHENOTYPES. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kuhn, D. E. et al. Chromosome 21-derived

microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains. _J. Biol. Chem._ 285, 1529–1543 (2010). Article  CAS  PubMed  Google Scholar  * Loudin,

M. G. et al. Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles. _Leukemia_ 25, 1555–1563 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Pletcher, M. T., Wiltshire, T., Cabin, D. E., Villanueva, M. & Reeves, R. H. Use of comparative physical and sequence mapping to

annotate mouse chromosome 16 and human chromosome 21. _Genomics_ 74, 45–54 (2001). Article  CAS  PubMed  Google Scholar  * Davisson, M. T. et al. Segmental trisomy as a mouse model for Down

syndrome. _Prog. Clin. Biol. Res._ 384, 117–133 (1993). THE CREATION OF THE FIRST VIABLE TRISOMIC MOUSE (TS65DN) WAS A REVOLUTION IN THE FIELD OF DOWN SYNDROME RESEARCH AND PROVIDED THE BEST

_IN VIVO_ MODEL FOR DOWN SYNDROME. ALSO SEE REFERENCE 82. CAS  PubMed  Google Scholar  * Reeves, R. H. et al. A mouse model for Down syndrome exhibits learning and behaviour deficits.

_Nature Genet._ 11, 177–184 (1995). Article  CAS  PubMed  Google Scholar  * Dierssen, M. et al. Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down

syndrome: effects of environmental enrichment. _Cereb. Cortex_ 13, 758–764 (2003). Article  CAS  PubMed  Google Scholar  * Sago, H. et al. Ts1Cje, a partial trisomy 16 mouse model for Down

syndrome, exhibits learning and behavioral abnormalities. _Proc. Natl Acad. Sci. USA_ 95, 6256–6261 (1998). Article  CAS  PubMed  PubMed Central  Google Scholar  * Villar, A. J. et al.

Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(171)65Dn and mouse chromosome 12. _Mamm.

Genome_ 16, 79–90 (2005). Article  CAS  PubMed  Google Scholar  * Ishihara, K. et al. Enlarged brain ventricles and impaired neurogenesis in the Ts1Cje and Ts2Cje mouse models of Down

syndrome. _Cereb. Cortex_ 20, 1131–1143 (2010). Article  PubMed  Google Scholar  * Olson, L. E. et al. Trisomy for the Down syndrome 'critical region' is necessary but not

sufficient for brain phenotypes of trisomic mice. _Hum. Mol. Genet._ 16, 774–782 (2007). THIS STUDY EXPLORED THE ROLE OF THE DSCR AND PRESENTED EVIDENCE THAT QUESTIONED THE DSCR HYPOTHESIS.

Article  CAS  PubMed  Google Scholar  * Belichenko, N. P. 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._ 29, 5938–5948 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Olson, L. E., Richtsmeier, J. T., Leszl, J. &

Reeves, R. H. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. _Science_ 306, 687–690 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Aldridge, K., Reeves, R. H., Olson, L. E. & Richtsmeier, J. T. Differential effects of trisomy on brain shape and volume in related aneuploid mouse models. _Am. J. Med. Genet. A_ 143A,

1060–1070 (2007). Article  PubMed  PubMed Central  Google Scholar  * Duchon, A. et al. The telomeric part of the human chromosome 21 from _Cstb_ to _Prmt2_ is not necessary for the locomotor

and short-term memory deficits observed in the Tc1 mouse model of Down syndrome. _Behav. Brain Res._ 217, 271–281 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  *

O'Doherty, A. et al. An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. _Science_ 309, 2033–2037 (2005). THIS PAPER DETAILS THE CREATION OF THE FIRST

'HUMANIZED' DOWN SYNDROME MOUSE MODEL. Article  CAS  PubMed  PubMed Central  Google Scholar  * Morice, E. et al. Preservation of long-term memory and synaptic plasticity despite

short-term impairments in the Tc1 mouse model of Down syndrome. _Learn. Mem._ 15, 492–500 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Galante, M. et al. Impairments in

motor coordination without major changes in cerebellar plasticity in the Tc1 mouse model of Down syndrome. _Hum. Mol. Genet._ 18, 1449–1463 (2009). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Reynolds, T. The triple test as a screening technique for Down syndrome: reliability and relevance. _Int. J. Womens Health_ 2, 83–88 (2010). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Li, Z. et al. Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal

abnormalities. _Hum. Mol. Genet._ 16, 1359–1366 (2007). Article  CAS  PubMed  Google Scholar  * Belichenko, P. V., Kleschevnikov, A. M., Salehi, A., Epstein, C. J. & Mobley, W. C.

Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. _J. Comp. Neurol._ 504, 329–345 (2007). Article  CAS  PubMed  Google

Scholar  * Escorihuela, R. M. et al. A behavioral assessment of Ts65Dn mice: a putative Down syndrome model. _Neurosci. Lett._ 199, 143–146 (1995). Article  CAS  PubMed  Google Scholar  *

Nambu, J. R., Lewis, J. O., Wharton, K. A. Jr & Crews, S. T. The _Drosophila_ single-minded gene encodes a helix-loop-helix protein that acts as a master regulator of CNS midline

development. _Cell_ 67, 1157–1167 (1991). Article  CAS  PubMed  Google Scholar  * Rachidi, M. et al. Spatial and temporal localization during embryonic and fetal human development of the

transcription factor _SIM2_ in brain regions altered in Down syndrome. _Int. J. Dev. Neurosci._ 23, 475–484 (2005). Article  CAS  PubMed  Google Scholar  * Chrast, R. et al. Mice trisomic

for a bacterial artificial chromosome with the single-minded 2 gene (_Sim2_) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome. _Hum.

Mol. Genet._ 9, 1853–1864 (2000). Article  CAS  PubMed  Google Scholar  * Chrast, R. et al. The mouse brain transcriptome by SAGE: differences in gene expression between P30 brains of the

partial trisomy 16 mouse model of Down syndrome (Ts65Dn) and normals. _Genome Res._ 10, 2006–2021 (2000). Article  CAS  PubMed  PubMed Central  Google Scholar  * Harashima, C. et al.

Elevated expression of the G-protein-activated inwardly rectifying potassium channel 2 (_GIRK2_) in cerebellar unipolar brush cells of a Down syndrome mouse model. _Cell. Mol. Neurobiol._

26, 719–734 (2006). Article  CAS  PubMed  Google Scholar  * Cooper, A. et al. Trisomy of the G protein-coupled K+ channel gene, _Kcnj6_, affects reward mechanisms, cognitive functions, and

synaptic plasticity in mice. _Proc. Natl Acad. Sci. USA_ 109, 2642–2647 (2012). Article  PubMed  PubMed Central  Google Scholar  * Alves-Sampaio, A., Troca-Marin, J. A. & Montesinos, M.

L. NMDA-mediated regulation of DSCAM dendritic local translation is lost in a mouse model of Down's syndrome. _J. Neurosci._ 30, 13537–13548 (2010). Article  CAS  PubMed  PubMed Central

  Google Scholar  * Gotti, S., Caricati, E. & Panzica, G. Alterations of brain circuits in Down syndrome murine models. _J. Chem. Neuroanat._ 42, 317–326 (2011). Article  CAS  PubMed 

Google Scholar  * Liu, C. et al. Mouse models for down syndrome-associated developmental cognitive disabilities. _Dev. Neurosci._ 33, 404–413 (2011). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Dierssen, M. et al. Murine models for Down syndrome. _Physiol. Behav._ 73, 859–871 (2001). Article  CAS  PubMed  Google Scholar  * Dierssen, M. & de Lagran, M. M.

DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A): a gene with dosage effect during development and neurogenesis. _ScientificWorldJournal_ 6, 1911–1922 (2006).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Smith, D. J., Zhu, Y., Zhang, J., Cheng, J. F. & Rubin, E. M. Construction of a panel of transgenic mice containing a contiguous

2-Mb set of YAC/P1 clones from human chromosome 21q22.2. _Genomics_ 27, 425–434 (1995). SMITH _ET AL_ . CREATED THE FIRST _IN VIVO_ LIBRARY OF MICE BEARING CONTIGUOUS PARTIAL TRISOMIES.

Article  CAS  PubMed  Google Scholar  * Guedj, F. et al. DYRK1A: a master regulatory protein controlling brain growth. _Neurobiol. Dis._ 46, 190–203 (2012). Article  CAS  PubMed  Google

Scholar  * Smith, D. J. & Rubin, E. M. Functional screening and complex traits: human 21q22.2 sequences affecting learning in mice. _Hum. Mol. Genet._ 6, 1729–1733 (1997). Article  CAS 

PubMed  Google Scholar  * Kleschevnikov, A. M. et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. _J.

Neurosci._ 24, 8153–8160 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yuste, R. Dendritic spines and distributed circuits. _Neuron_ 71, 772–781 (2011). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Dierssen, M. & Ramakers, G. J. Dendritic pathology in mental retardation: from molecular genetics to neurobiology. _Genes Brain Behav._ 5, 48–60

(2006). Article  CAS  PubMed  Google Scholar  * Galdzicki, Z. & Siarey, R. J. Understanding mental retardation in Down's syndrome using trisomy 16 mouse models. _Genes Brain

Behav._ 2, 167–178 (2003). Article  CAS  PubMed  Google Scholar  * Siarey, R. J., Stoll, J., Rapoport, S. I. & Galdzicki, Z. Altered long-term potentiation in the young and old Ts65Dn

mouse, a model for Down Syndrome. _Neuropharmacology_ 36, 1549–1554 (1997). Article  CAS  PubMed  Google Scholar  * Kurt, M. A., Davies, D. C., Kidd, M., Dierssen, M. & Florez, J.

Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice. _Brain Res._ 858, 191–197 (2000). THIS IS THE FIRST PAPER DESCRIBING THE EXCITATION–INHIBITION IMBALANCE IN THE

HIPPOCAMPUS OF A DOWN SYNDROME TRISOMIC MOUSE MODEL (TS65DN). Article  CAS  PubMed  Google Scholar  * Pereira, P. L. et al. A new mouse model for the trisomy of the _Abcg1−U2af1_ region

reveals the complexity of the combinatorial genetic code of down syndrome. _Hum. Mol. Genet._ 18, 4756–4769 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Martinez de

Lagran, M. et al. Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. _Cereb. Cortex_ 2 Jan 2012 (doi:10.1093/cercor/bhr362).

* Kurt, M. A., Kafa, M. I., Dierssen, M. & Davies, D. C. Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome.

_Brain Res._ 1022, 101–109 (2004). Article  CAS  PubMed  Google Scholar  * Belichenko, P. V. et al. Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down

syndrome. _J. Comp. Neurol._ 512, 453–466 (2009). Article  PubMed  PubMed Central  Google Scholar  * Siarey, R. J. et al. Increased synaptic depression in the Ts65Dn mouse, a model for

mental retardation in Down syndrome. _Neuropharmacology_ 38, 1917–1920 (1999). Article  CAS  PubMed  Google Scholar  * Popov, V. I., Kleschevnikov, A. M., Klimenko, O. A., Stewart, M. G.

& Belichenko, P. V. Three-dimensional synaptic ultrastructure in the dentate gyrus and hippocampal area CA3 in the Ts65Dn mouse model of Down syndrome. _J. Comp. Neurol._ 519, 1338–1354

(2011). Article  CAS  PubMed  Google Scholar  * Escorihuela, R. M. et al. Early environmental stimulation produces long-lasting changes on β-adrenoceptor transduction system. _Neurobiol.

Learn. Mem._ 64, 49–57 (1995). Article  CAS  PubMed  Google Scholar  * Coussons-Read, M. E. & Crnic, L. S. Behavioral assessment of the Ts65Dn mouse, a model for Down syndrome: altered

behavior in the elevated plus maze and open field. _Behav. Genet._ 26, 7–13 (1996). Article  CAS  PubMed  Google Scholar  * Hyde, L. A., Crnic, L. S., Pollock, A. & Bickford, P. C. Motor

learning in Ts65Dn mice, a model for Down syndrome. _Dev. Psychobiol._ 38, 33–45 (2001). Article  CAS  PubMed  Google Scholar  * Driscoll, L. L. et al. Impaired sustained attention and

error-induced stereotypy in the aged Ts65Dn mouse: a mouse model of Down syndrome and Alzheimer's disease. _Behav. Neurosci._ 118, 1196–1205 (2004). Article  PubMed  Google Scholar  *

Escorihuela, R. M. et al. Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome. _Neurosci. Lett._ 247, 171–174 (1998). Article  CAS  PubMed  Google Scholar  *

Martinez-Cue, C. et al. Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome. _Behav. Brain Res._ 134, 185–200

(2002). Article  PubMed  Google Scholar  * Baamonde, C., Martinez-Cue, C., Florez, J. & Dierssen, M. G-protein-associated signal transduction processes are restored after postweaning

environmental enrichment in Ts65Dn, a Down Syndrome mouse model. _Dev. Neurosci._ 33, 442–450 (2011). Article  CAS  PubMed  Google Scholar  * Casanova, M. F., Walker, L. C., Whitehouse, P.

J. & Price, D. L. Abnormalities of the nucleus basalis in Down's syndrome. _Ann. Neurol._ 18, 310–313 (1985). Article  CAS  PubMed  Google Scholar  * Mann, D. M., Yates, P. O. &

Hawkes, J. The pathology of the human locus ceruleus. _Clin. Neuropathol._ 2, 1–7 (1983). CAS  PubMed  Google Scholar  * Salehi, A. et al. Restoration of norepinephrine-modulated contextual

memory in a mouse model of Down syndrome. _Sci. Transl. Med._ 1, 7ra17 (2009). Article  CAS  PubMed  Google Scholar  * Chang, Q. & Gold, P. E. Age-related changes in memory and in

acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome. _Neurobiol. Learn. Mem._ 89, 167–177 (2008). Article  CAS  PubMed  Google Scholar  * Rueda, N.,

Florez, J. & Martinez-Cue, C. Effects of chronic administration of SGS-111 during adulthood and during the pre- and post-natal periods on the cognitive deficits of Ts65Dn mice, a model

of Down syndrome. _Behav. Brain Res._ 188, 355–367 (2008). Article  CAS  PubMed  Google Scholar  * Holtzman, D. M. et al. Developmental abnormalities and age-related neurodegeneration in a

mouse model of Down syndrome. _Proc. Natl Acad. Sci. USA_ 93, 13333–13338 (1996). Article  CAS  PubMed  PubMed Central  Google Scholar  * Prasher, V. P., Fung, N. & Adams, C.

Rivastigmine in the treatment of dementia in Alzheimer's disease in adults with Down syndrome. _Int. J. Geriatr. Psychiatry_ 20, 496–497 (2005). Article  CAS  PubMed  Google Scholar  *

Van der Molen, M. J. et al. Attentional set-shifting in fragile X syndrome. _Brain Cogn._ 78, 206–217 (2012). Article  CAS  PubMed  Google Scholar  * Hanson, J. E., Blank, M., Valenzuela, R.

A., Garner, C. C. & Madison, D. V. The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome. _J. Physiol._ 579,

53–67 (2007). Article  CAS  PubMed  Google Scholar  * Fagiolini, M. & Hensch, T. K. Inhibitory threshold for critical-period activation in primary visual cortex. _Nature_ 404, 183–186

(2000). Article  CAS  PubMed  Google Scholar  * Southwell, D. G., Froemke, R. C., Alvarez-Buylla, A., Stryker, M. P. & Gandhi, S. P. Cortical plasticity induced by inhibitory neuron

transplantation. _Science_ 327, 1145–1148 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of

Down syndrome. _Nature Neurosci._ 10, 411–413 (2007). Article  CAS  PubMed  Google Scholar  * Rueda, N., Florez, J. & Martinez-Cue, C. Chronic pentylenetetrazole but not donepezil

treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome. _Neurosci. Lett._ 433, 22–27 (2008). Article  CAS  PubMed  Google Scholar  * Owens, D. F. & Kriegstein, A.

R. Developmental neurotransmitters? _Neuron_ 36, 989–991 (2002). Article  CAS  PubMed  Google Scholar  * Baroncelli, L. et al. Brain plasticity and disease: a matter of inhibition. _Neural

Plast._ 2011, 286073 (2011). Article  PubMed  PubMed Central  Google Scholar  * Owens, D. F. & Kriegstein, A. R. Is there more to GABA than synaptic inhibition? _Nature Rev. Neurosci._

3, 715–727 (2002). Article  CAS  Google Scholar  * Becker, L., Mito, T., Takashima, S. & Onodera, K. Growth and development of the brain in Down syndrome. _Prog. Clin. Biol. Res._ 373,

133–152 (1991). CAS  PubMed  Google Scholar  * Braudeau, J. et al. Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down

syndrome mice. _J. Psychopharmacol._ 25, 1030–1042 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Costa, A. C., Scott-McKean, J. J. & Stasko, M. R. Acute injections of

the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. _Neuropsychopharmacology_ 33, 1624–1632 (2008).

Article  CAS  PubMed  Google Scholar  * Lockrow, J., Boger, H., Bimonte-Nelson, H. & Granholm, A. C. Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model

for Down syndrome. _Behav. Brain Res._ 221, 610–622 (2011). Article  CAS  PubMed  Google Scholar  * Rueda, N. et al. Memantine normalizes several phenotypic features in the Ts65Dn mouse

model of Down syndrome. _J. Alzheimers Dis._ 21, 277–290 (2010). Article  CAS  PubMed  Google Scholar  * Marvanova, M. et al. The neuroprotective agent memantine induces brain-derived

neurotrophic factor and trkB receptor expression in rat brain. _Mol. Cell. Neurosci._ 18, 247–258 (2001). Article  CAS  PubMed  Google Scholar  * Westmark, C. J. et al. Reversal of fragile X

phenotypes by manipulation of AβPP/Aβ levels in _Fmr1_KO mice. _PLoS ONE_ 6, e26549 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lorenzi, H. A. & Reeves, R. H.

Hippocampal hypocellularity in the Ts65Dn mouse originates early in development. _Brain Res._ 1104, 153–159 (2006). Article  CAS  PubMed  Google Scholar  * Bianchi, P. et al. Early

pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome. _J. Neurosci._ 30, 8769–8779 (2010). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Roper, R. J. et al. Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice. _Proc. Natl Acad. Sci. USA_ 103, 1452–1456 (2006). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Delcroix, J. D. et al. Trafficking the NGF signal: implications for normal and degenerating neurons. _Prog. Brain Res._ 146, 3–23 (2004). CAS 

PubMed  Google Scholar  * Salehi, A., Faizi, M., Belichenko, P. V. & Mobley, W. C. Using mouse models to explore genotype-phenotype relationship in Down syndrome. _Ment. Retard. Dev.

Disabil. Res. Rev._ 13, 207–214 (2007). Article  PubMed  Google Scholar  * Tejedor, F. J. & Hammerle, B. MNB/DYRK1A as a multiple regulator of neuronal development. _FEBS J._ 278,

223–235 (2011). Article  CAS  PubMed  Google Scholar  * Hammerle, B. et al. Transient expression of _Mnb/Dyrk1a_ couples cell cycle exit and differentiation of neuronal precursors by

inducing _p27_KIP1 expression and suppressing NOTCH signaling. _Development_ 138, 2543–2554 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yabut, O., Domogauer, J. &

D'Arcangelo, G. Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells. _J. Neurosci._ 30, 4004–4014 (2010). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Ortiz-Abalia, J. et al. Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of Down syndrome. _Am. J. Hum.

Genet._ 83, 479–488 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Guedj, F. et al. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. _PLoS

ONE_ 4, e4606 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gockler, N. et al. Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation.

_FEBS J._ 276, 6324–6337 (2009). Article  CAS  PubMed  Google Scholar  * Mazur-Kolecka, B. et al. Effect of DYRK1A activity inhibition on development of neuronal progenitors isolated from

Ts65Dn mice. _J. Neurosci. Res._ 90, 999–1010 (2012). Article  CAS  PubMed  Google Scholar  * Kamenetz, F. et al. APP processing and synaptic function. _Neuron_ 37, 925–937 (2003). Article 

CAS  PubMed  Google Scholar  * Netzer, W. J. et al. Lowering β-amyloid levels rescues learning and memory in a Down syndrome mouse model. _PLoS ONE_ 5, e10943 (2010). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Chakrabarti, L. et al. _Olig1_ and _Olig2_ triplication causes developmental brain defects in Down syndrome. _Nature Neurosci._ 13, 927–934 (2010). THE

AUTHORS IDENTIFIED OLIG1 AND OLIG2 AS IMPORTANT PLAYERS IN THE DEVELOPMENTAL ALTERATIONS, LEADING TO INCREASED INHIBITION IN DOWN SYNDROME. Article  CAS  PubMed  Google Scholar  * Haydar, T.

F. & Reeves, R. H. Trisomy 21 and early brain development. _Trends Neurosci._ 35, 81–91 (2012). Article  CAS  PubMed  Google Scholar  * Edgin, J. O. et al. Development and validation of

the Arizona Cognitive Test Battery for Down syndrome. _J. Neurodev Disord._ 2, 149–164 (2010). THE ARIZONA COGNITIVE TEST BATTERY IS THE FIRST SERIOUS ATTEMPT TO CREATE A NEUROPSYCHOLOGICAL

EXPLORATION SCREEN THAT IS SPECIFIC FOR DOWN SYNDROME. Article  PubMed  PubMed Central  Google Scholar  * Nadel, L. Down's syndrome: a genetic disorder in biobehavioral perspective.

_Genes Brain Behav._ 2, 156–166 (2003). Article  CAS  PubMed  Google Scholar  * Ponting, C. P. & Belgard, T. G. Transcribed dark matter: meaning or myth? _Hum. Mol. Genet._ 19, R162–R168

(2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Elton, T. S., Sansom, S. E. & Martin, M. M. Trisomy-21 gene dosage over-expression of miRNAs results in the

haploinsufficiency of specific target proteins. _RNA Biol._ 7, 540–547 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Senti, K. A. & Brennecke, J. The piRNA pathway: a

fly's perspective on the guardian of the genome. _Trends Genet._ 26, 499–509 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Singh Sandhu, K., Li, G., Sung, W. K. &

Ruan, Y. Chromatin interaction networks and higher order architectures of eukaryotic genomes. _J. Cell. Biochem._ 112, 2218–2221 (2011). Article  CAS  PubMed  Google Scholar  * Reinholdt, L.

G. et al. Meiotic behavior of aneuploid chromatin in mouse models of Down syndrome. _Chromosoma_ 118, 723–736 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Cramer, N.

& Galdzicki, Z. From abnormal hippocampal synaptic plasticity in down syndrome mouse models to cognitive disability in down syndrome. _Neural Plast._ 2012, 101542 (2012). Article  PubMed

  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This Review is dedicated to all people with Down syndrome. I also dedicate it to M. Flórez and E. Bishop, and I offer a

special thank you to J. Flórez, who is the professor that directed me to the field of Down syndrome research. I thank M. Martínez de Lagrán, G. Azkona and G. Arqué for their contributions

to putting together the movies, and D. D'Amico for his contribution to figure 1. I apologize to all those colleagues whose work could not be cited directly in the manuscript due to

space constraints. The work from my laboratory that is mentioned here was possible thanks to grants and contributions from the Jerôme Lejeune Foundation, Fundació Catalana Síndrome de Down,

the Catalan Government (2009SGR1313), Spanish Ministry of Education and Sciences (SAF2007-60827, SAF2007-31093-E and SAF2010-16427), EU/FIS (PS09102673), CureFXS, ERARare, Fundación Ramón

Areces, Alicia Koplowtiz, Marató TV3 and the Centre for Biomedical Network Research on Rare Diseases. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Genes and Disease Programme, Centre for

Genomic Regulation (CRG); Universitat Pompeu Fabra (UPF), Mara Dierssen * Universitat Pompeu Fabra (UPF), Mara Dierssen * Centro de Investigación Biomédica en Red de Enfermedades Raras

(CIBERER), Dr. Aiguader 88, Barcelona, E-08003, Spain Mara Dierssen Authors * Mara Dierssen View author publications You can also search for this author inPubMed Google Scholar ETHICS

DECLARATIONS COMPETING INTERESTS The author declares no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION S1 (MOVIE) The Tapping test is part of the Wechsler

Memory Scale-Revised and it is an adaptation of the Corsi-Block Tapping test (Orsini, A. Corsi’s block-tapping test: standardization and concurrent validity with WISC-R for children aged 11

to 16. _Percept. Mot. Skills_ 79, 1547–1554 (1994)). It allows the study of the hippocampus-dependent visual-spatial declarative memory but also reflects attentional capacity, visual

perceptive organization and executive functioning. This test is broadly used to define these specific abilities in different intellectual disability syndromes. Even though more sophisticated

techniques are used now and computer versions of this test are available, the original version still provides very useful information. Briefly, the participants are presented in series with

'_n_' elements. In the absence of any difference between the shape and colour of the cubes, the spatial component is the most relevant. Sequences to be reproduced are randomly

selected through a computer program, taking into account that the different spatial configurations provide a similar level of difficulty. Spatial memory is assessed by analysing the errors

in reproducing the correct sequence of element taps. In general, the best recalled items in the series are the initial and final items (primacy and recency effect). Movie S1 shows a correct

reproduction of the series by a healthy volunteer after the experimenter’s demonstration. The numbers are shown to the experimenter but are not visible for the participant. (MP4 314 kb)

SUPPLEMENTARY INFORMATION S2 (MOVIE) Movie S2 shows the same series demonstrated by the experimenter in Movie S1, but here the healthy volunteer is not reproducing the series correctly.

Instead the volunteer is demonstrating a typical visuospatial error, not maintaining the spatial configuration presented. Random errors or inclusion of an element that is not present in the

series are also frequent in populations with intellectual disability. (MP4 364 kb) SUPPLEMENTARY INFORMATION S3 (MOVIE) Neuritogenesis in wild-type mice. The movie shows phase contrast

time-lapse experiments performed to analyse axon growth in EGFP-transfected cultured cortical neurons derived from a 17.5-day-old wild-type mouse embryo (Martinez de Lagran, M. _et al_.

Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. _Cereb. Cortex_ 2 Jan 2012 (doi: 10.1093/cercor/bhr362)). Images were

acquired at DIV 1 every 5 min for a period of 14 hours using 40 ms integration time to record stage coordinates of suitable axonal growth cones and analysed with particle track plugging of

Image J software. (AVI 64555 kb) SUPPLEMENTARY INFORMATION S4 (MOVIE) Neuritogenesis in Down syndrome. The movie shows phase contrast time-lapse experiments performed to analyse axon growth

in EGFP-transfected cultured cortical neurons derived from a 17.5-day-old _Dyrk1A_-overexpressing (TgDyrk1A) embryo. Images were acquired as described for Movie S3. Note that the axonal

behaviour is different in transgenic neurons, which showed a significant reduction in the distance travelled by the axon leading to reduced axonal elongation, a phenotype that is also

detected in Down syndrome (for detailed explanation, see Martinez de Lagran, M. _et al_. Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian

cortical neurons. _Cereb. Cortex_ 2 Jan 2012 (doi: 10.1093/cercor/bhr362)). TgDyrk1A neurons presented with shorter terminal segments and less complex dendritic arbors with fewer dendrites,

branch points and terminal segments. Mature synapse formation is reduced in the TgDyrk1A mouse, where filopodia-like spines are more abundant and mature spines are reduced in number

(Martinez de Lagran, M. _et al_. Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. _Cereb. Cortex_ 2 Jan 2012 (doi:

10.1093/cercor/bhr362); Popov, V. I., Kleschevnikov, A. M., Klimenko, O. A., Stewart, M. G. & Belichenko, P. V. Three-dimensional synaptic ultrastructure in the dentate gyrus and

hippocampal area CA3 in the Ts65Dn mouse model of Down syndrome. _J. Comp. Neurol_. 519, 1338–1354 (2011); Tejedor, F. J. & Hammerle, B. MNB/DYRK1A as a multiple regulator of neuronal

development. _FEBS J_. 278, 223–235 (2011); Belichenko, P. V. _et al_. Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome. _J. Comp. Neurol_. 480, 281–298 (2004)).

(AVI 44186 kb) RELATED LINKS RELATED LINKS FURTHER INFORMATION Mara Dierssen's homepage Down Syndrome International: Research and Practice Down Syndrome Research and Treatment

Foundation Gene Function and Pathway Databases — GFuncPathdb The HSA21 expression map initiative: a gene expression map of HSA21 orthologues in the mouse Jerôme Lejeune Foundation The

National Down syndrome Congress Online Mendelian Inheritance in Man: Down syndrome GLOSSARY * Intellectual disability A disability that is characterized by significant limitations both in

intellectual functioning and in adaptive behaviour. * Working memory A system that is involved in the temporary storage and ongoing maintenance of information. * Long-term memory A memory

system for more permanently storing, managing and retrieving information for later use. * Explicit memory This is the conscious processing of information to remember it following a delay. *

Implicit memory This comprises an unconscious, slower learning system, in which a previous experience influences current behaviour without consciousness of the first episode. * Brachycephaly

A condition in which an individual has an abnormally broad and short head, which occurs when the coronal sutures close prematurely. * Plasticity This is defined as the capacity of the

nervous system to modify its structural and functional organization as a result of experience. * Cognition This is considered to be the process or processes whereby an organism gains

knowledge or becomes aware of events or objects in its environment and uses that knowledge for comprehension and problem solving. * Small non-coding RNAs These are regulatory genomic

elements that are 18–30 nucleotides in length and include microRNAs, PIWI-interacting RNAs and endogenous small interfering RNAs. * Cerebral cortex This is the outermost layer of the

cerebral hemispheres of the brain and is largely responsible for all forms of conscious experience, including perception, emotion, thought and planning. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Dierssen, M. Down syndrome: the brain in trisomic mode. _Nat Rev Neurosci_ 13, 844–858 (2012). https://doi.org/10.1038/nrn3314 Download

citation * Published: 20 November 2012 * Issue Date: December 2012 * DOI: https://doi.org/10.1038/nrn3314 SHARE THIS ARTICLE Anyone you share the following link with will be able to read

this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative