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.
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.
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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.
The author declares no competing financial interests.
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)
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)
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)
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)
- 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.
A condition in which an individual has an abnormally broad and short head, which occurs when the coronal sutures close prematurely.
This is defined as the capacity of the nervous system to modify its structural and functional organization as a result of experience.
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.
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Dierssen, M. Down syndrome: the brain in trisomic mode. Nat Rev Neurosci 13, 844–858 (2012). https://doi.org/10.1038/nrn3314
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