They describe how Down syndrome alters brain development before birth

The Down syndrome alters the development of the human brain before birth and now a team of researchers has created a molecular map that explains how, which could serve to develop therapeutic strategies in the future. A team of researchers led by Ecuadorian, Luis De la Torre-Ubieta, from the University of California-Los Angeles (UCLA), has analyzed 100,000 nuclei from prenatal cerebral neocortex samples of 26 human donors with Down syndrome. The samples corresponded to gestational weeks 13 to 23, a key period during which all the cortical neurons that a person will have throughout their life are generated. The findings, published this Thursday in the Science journal, suggest that Down syndrome alters the sequence of development of the process of cortical neuron formation, creating changes that would explain the difficulties in cognition, learning, and sensory processing that these people later experience.

“For the first time, we have understood in great detail what happens in the developing brain of people with Down syndrome,” underlines Torre-Ubieta, researcher at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Addressing a Fundamental Gap

The field of research on Down syndrome has historically focused on two areas: the adult brain and the relationship of the disorder to neurodegeneration. The vast majority of people with Down syndrome develop Alzheimer's disease from the age of 60. What remained undeciphered in humans is how the condition shapes the developing brain itself. Now, Torre-Ubieta's team has achieved this thanks to the molecular mapping achieved through the samples. To understand this, one must start from the basis that the development of the prenatal neocortex usually follows a strictly coordinated sequence.

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First, the progenitor cells or stem cells of the brain must divide repeatedly to expand their own set. Only then do they begin to differentiate into neurons, starting with the cell types of the deep layer and moving towards those of the upper layer of the brain in a carefully synchronized order. In Down syndrome, that sequence appears to break down, according to researchers. Progenitor cells rush prematurely into neuron production, depleting their own pool and disrupting the balance of neuron types generated. That precipitation causes an increase in intratelencephalic neurons in the upper layer of the brain and a reduction in corticothalamic neurons in the deep layer, which in the future will translate into cognitive, learning, and sensory processing difficulties.

The discovery also offers a new answer to why people with Down syndrome tend to have smaller brains: due to the premature exhaustion of the progenitor cell pool.

Implications

The authors specifically analyzed the overlap between the molecular alterations they identified and the genetic risk signatures associated with other neurological conditions such as autism, epilepsy, and developmental delay, finding "substantial convergence".

"Down syndrome could be a model for understanding the common biology underlying these conditions, as the mechanisms often remain unknown," points out the Ecuadorian researcher.

This same edition of Science includes another article in which researchers from the American University of Wisconsin-Madison examine the postnatal brain of people with Down syndrome between 1 and 5 years of age. When the two scientific groups shared their findings, they discovered great parallels: many of the changes identified prenatally seem to persist in early childhood. Together, the two articles offer a continuous molecular view of brain development in Down syndrome from mid-pregnancy to early childhood that will be a reference for science in the coming years. Although the findings do not point to a short-term clinical application, Torres-Ubieta believes that these "therapeutic targets could be harnessed in the future to develop drugs for specific pathways, or gene therapies to avoid these alterations in brain development.