Reacción a "A cellular map reveals how Down syndrome affects prenatal brain development"

Down syndrome (DS) is the most common genetic cause (1 in 700–1,000 births) of intellectual disability. Although it has been known for nearly 70 years that it results from the triplication of chromosome 21 (trisomy 21, TS21), its genetic complexity (approximately 250 coding genes and several hundred non-coding RNAs tripled in the first instance, with the regulation of thousands of them on other chromosomes consequently affected) has hindered progress in understanding the alterations in the cellular and molecular mechanisms that lead to the neurodevelopmental problems associated with DS.

Some neurohistological and imaging studies have shown significant changes in the cellular architecture of prenatal brains, particularly in the neocortex, of individuals with Ts21. This indicates that cellular processes of neurodevelopment are disrupted very early in DS, a finding also supported by research conducted using animal models (primarily mice). However, it should be noted that the limitations of these animal models—namely, their inability to reproduce human chromosomal organization, as well as some significant differences in the neurogenesis processes of the cerebral cortex (the region of the brain that is arguably the most evolved and developed in humans)—have prevented a precise determination of the cellular and molecular processes of early neurodevelopment altered by TS21.

Researchers at the University of California, Los Angeles (UCLA) have published a study in the journal Science that addresses precisely this problem. They have used genomic techniques that allow the identification, in individual cells, of both the genes that are expressed and the open chromatin regions—that is, areas of the genome available for activation. By applying these methods to dissociated cerebral cortex cells throughout the second trimester of fetal development (a crucial period for the generation of cortical neurons) in control brains and those with TS21, they were able to identify the DS-associated alterations occurring in the cell populations generated during that period.

The study clearly concludes that DS extensively affects the temporal sequence of cell population generation in the neocortex, leading to a decrease in the initial population of neural progenitor cells and premature neurogenesis, which could explain the well-known neuronal deficit in DS. More importantly, these changes result in an alteration of the spatiotemporal pattern of neuron production, which occur in successive layers from the inside out. This pattern is fundamental for the specification of neuronal populations that integrate into distinct cortical circuits depending on the timing of their birth and the position they occupy. Notably, in the neocortex with Ts21, there is a loss of balance between populations of excitatory neurons, with an increase in those occupying superficial layers—which participate in local circuits—at the expense of those located in deep layers, which connect to other brain regions. Furthermore, analysis of the collected genomic data allows for the prediction of potential gene regulatory networks altered by TS21 during this period of neurodevelopment.

Overall, the insights provided by this study are of immense value for advancing research into the fundamental causes of neurodevelopmental alterations caused by DS, and the possibility that it may help identify new therapeutic targets should not be overlooked. However, the possibility that this knowledge will translate into the development of therapeutic strategies to counteract early neurodevelopmental alterations in DS should be viewed with caution, at least in the short term, not only because of the various difficulties inherent in any intervention during the prenatal period, but also because the intricate networks of gene interactions altered by Trisomy 21—which the study itself confirms (2–10% of genes differentially expressed across all chromosomes)—make the hypothetical restoration of these processes to their normal course extremely difficult.