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• W1977936302 abstract "Down's syndrome (DS) is the most common genetic birth defect associated with mental retardation. In addition to the patients, their parents, other family members and carers are also heavily affected socially, emotionally and economically. Some critical issues have recently lead to a significant progress in DS basic research: the improved knowledge of molecular genetics, the implementation of functional imaging analysis and the generation of valuable experimental models, have sped up our understanding of the relevant molecular pathways that determine how the brain circuitry is sculpted during development in this genetic disorder. This will provide a solid knowledge base for the emergence of concepts regarding the structural and functional alterations associated with DS and an important perspective for thinking about therapy. DS is the consequence of the presence of an extra copy of all or part of human chromosome 21 (HSA21). While some loci may have a greater phenotypic effect, it is the cumulative effect of the imbalance of many genes that determines the overall phenotype. In addition, an accumulating body of evidence indicates that genes located on other chromosomes are also involved in the process. Different hypotheses have been proposed to explain this mystery: (i) the amplified developmental instability hypothesis (Shapiro 2001) suggests that DS is the result of a non-specific disturbance of chromosome balance, resulting in a disruption of homeostasis and (ii) the gene dosage hypothesis proposes that DS phenotypes may stem directly from the cumulative effect of overexpression of specific chromosome 21 gene products or indirectly through the interaction of these HSA21 genes products with the whole genome, transcriptome or proteome. Although DS is undoubtedly a specific case of the more general problem of explaining how chromosomal imbalance produces abnormalities in morphology and function, overexpression of genes residing in HSA21 is considered to be the central point for the DS phenotype. The enormous amount of new molecular and biological data that has developed for HSA21 as a result of the human genome initiative (Hattori et al. 2000) has sped up the understanding of the molecular and cellular basis of mental retardation, and will have an immediate impact on the study of the genetic aspects of DS by providing a comprehensive catalogue of the genes on HSA21. The gene content of chromosome 21 is now estimated to be 329, including 165 experimentally confirmed genes, 150 gene models based on expressed sequence tag databases and 14 computer predictions (see http://www-eri.uchsc.edu). Several anonymous loci for monogenic disorders and predispositions for common complex disorders have also been mapped to HSA21. However, the functions of most of these genes remain largely unknown, as does their contribution, if any, to DS. The phenotypic consequences of increased gene dosage depend, in part, on the biological function of the gene product itself (e.g. enzyme, structural protein, transcription factor, intracellular signaling molecule, cell surface marker, receptor subunit, etc.). An additional, unexpected finding is that the actual fraction of the genomic sequence of HSA21 that is transcribed into RNA might be an order of magnitude higher than the fraction occupied by the predicted and characterized gene coding sequences (Kapranov et al. 2002). The answer to the question of what function these transcripts might have requires additional large-scale characterization of the observed novel transcripts. Finally, efforts to generate gene expression data for the of 21q genes have lead to the creation of a high resolution expression ‘atlas’ of HSA21, an important step towards the understanding of gene function and of the pathogenetic mechanisms in Down's syndrome (Gitton et al. 2002; Reymond et al. 2002). The spatial and temporal expression patterns must be linked to structural and physiological changes, information that will shed light on the roles of individual genes in specific developmental pathways. The crucial question, however, is to define how development differs from normal in genetic disorders. In addition, how does an excess of normal gene products in interaction with other genes, gene products and with the environment, direct and constrain neural maturation and how does this maldevelopment translate into minds and behavior. Our understanding of how an extra copy of HSA21 leads to the development of microcephaly, cognitive and language impairment, and neuromotor dysfunction (hypotonia, diminished reflexes and motor delays) remains poor. In this special interest section Lynn Nadel points out that any answer to this question starts with the profound analysis of neural development in DS and normal brains (Nadel 2003). The overexpression of specific genes of HSA21 results in altered patterns of histoanatomical and/or physiological development and maturation of the CNS. The function of these genes and/or protein products has been partially characterized, and many are being tested to determine their role in the neuropathogenesis of DS. Ultimately, the effects of gene dosage imbalance must be understood within the framework of those critical developmental events that regulate brain organisation and function. The increase in the use of functional neuroimaging techniques in these pathologies has improved our knowledge of the neuroanatomical basis of brain malfunctioning in DS human brains and provided initial clues as to the specific defects that occur in DS during neural development. This approach offers the opportunity to understand which brain structures are implicated in specific neurobehavioral conditions and may also yield insight into the question of individual variation among persons with the same neurogenetic syndrome. Recently, in vivo structural brain imaging in young DS adults and post-mortem studies indicate smaller overall brain volumes with disproportionately smaller cerebellar and frontal lobe volumes (Pinter et al. 2001) but after correction for height, brain size is normal. Functional imaging with PET shows normal brain glucose metabolism, but fewer significant correlations between metabolic rates in different brain regions than in controls, suggesting reduced functional connections between brain circuit elements. Some of these alterations may be related to an abnormal development of the nervous system during pre- and postnatal life. In fetuses, a reduction in the width of the cortex and abnormal cortical lamination patterns, altered dendritic arbors and dendritic spines, altered electrophysiological properties of membranes, reduced synaptic density and abnormal synaptic morphology have been described (see Kaufmann & Moser 2000 for review). Much of our knowledge of the neurodevelopmental period is based on studies of the inability of children with DS to acquire and ‘stabilize’ the information that they do manage to learn, which might reflect impairments in learning processes and memory consolidation (see Nadel 2003). Zygmunt Galdzicki in his paper (Galdzicki 2003) raises the question of whether the neural networks that are built from trisomy 21 neurons are less optimized, and thus likely to be less adaptable and less able to perform efficiently their respective tasks than similar networks of diploid neurons, as genetic information contained in each neuronal nucleus is sufficient to preprogram all of the connections in the human brain, and because patterns of electrical neuronal activity determine our perception, thoughts, memories and ability to learn (Rees et al. 2002). Gradual developmental impact of the initial genetic insults caused by trisomy 21 in the single cell causes downstream effects through abnormal gene expression (Reeves et al. 2001). This in turn adds the temporal dimension to the process that results in specific DS traits. It is probably true that genome-based plasticity is decreased in DS, and thus the finding of specific genes with a role in the maturation and neural plasticity will allow the design of novel therapeutic approaches. A better understanding of DS neuronal networks will enhance the understanding of cognitive processes, and to achieve this goal animal models have enormous potential to elucidate mental retardation mechanisms that may be acting in humans. Studies with the various trisomy mouse models at different developmental stages can recreate certain conditions that result in abnormal learning capabilities in DS. Previous work with animal models of DS has found abnormalities of cortical volume, lamination, proliferation and connectivity during the fetal period and has led to the proposal that similar abnormalities occur in DS patients. Changes in timing and synaptic interaction between neurons during development can lead to less than optimal functioning of neural circuitry and signaling at that time and in later life. Adult segmental trisomy 16 mice (Ts65Dn) demonstrate abnormalities in synaptic plasticity and evidence suggests that the abnormalities in the trisomy mouse models are related to defective signal transduction pathways involving the phosphoinositide cycle, protein kinase A and protein kinase C. Animal models for DS can be used to study the mechanisms of brain responses to different types of pharmacological and non-pharmacological intervention. Several recent reviews of the effectiveness of early intervention in DS have concluded that, despite benefits in social adaptive function, any effects on cognition (as measured by IQ) are limited, and temporary. In the Ts65Dn mice, responses to environmental enrichment applied for 6 weeks just after weaning at the behavioral level are positive in a sex-dependent manner (Martinez-Cuéet al. 2002). The finding of dendritic pathology as a distinctive feature of Ts65Dn mice and the lack of response to environmental changes supports the concept that dendritic abnormalities are an index of major neuronal disruption and may be the major substrate for the instability of the environmental effects observed in DS patients (Dierssen et al. in press). The recovery of cognitive capacities in DS patients is a challenge and will rely on identifying good candidate genes and on including the impact of environmental and contextual factors into genetic designs. Finally, a continuous search for new more specific and accurate experimental approaches is fundamental in DS research. As stated by Anita Bhattacharyya and Clive N. Svendsen in this special interest section (Bhattacharyya & Svendsen 2003) although mouse models of DS have provided a useful way of studying DS neural development, there are clearly significant differences between rodent and human biology. Recent advances in stem cell biology now allow the generation of human neural tissue in the culture dish (Ostenfeld & Svendsen 2003). Neural stem and progenitor cells derived from trisomy 21 cortex have shown that the expression patterns of specific genes not associated with HSA21 are changed during cortical development (Bhattacharyya & Svendsen 2003). These neurosphere cultures hold promise as the way to define specific genetic changes that occur during formation of the cerebral cortex in DS. The recent advances in genomic analysis of HSA21 have provided valuable information that has determined, in recent years, the most important advances in the history of DS research. These advances have provided the tools for the understanding of the molecular basis of DS neuropathology, through the analysis of model organisms and cultured cells. More importantly, new, specific targets for molecular diagnosis and therapeutic interventions will become available for investigation. However, although exciting new findings will emerge in the near future, we are still far from completely understanding the syndrome, and by extension the molecular basis of the pathology and physiology of the cognitive processes." @default.
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• W1977936302 date "2003-06-01" @default.
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• W1977936302 title "Special interest section - Down's syndrome: postgenomic approaches to neurobiological problems" @default.
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