Consequences of trisomy 21 for brain development in Down syndrome

Abstract

The appearance of cognitive deficits and altered brain morphology in newborns with Down syndrome (DS) suggests that these features are driven by disruptions at the earliest stages of brain development. Despite its high prevalence and extensively characterized cognitive phenotypes, relatively little is known about the cellular and molecular mechanisms that drive the changes seen in DS. Recent technical advances, such as single-cell omics and the development of induced pluripotent stem cell (iPSC) models of DS, now enable in-depth analyses of the biochemical and molecular drivers of altered brain development in DS. Here, we review the current state of knowledge on brain development in DS, focusing primarily on data from human post-mortem brain tissue. We explore the biological mechanisms that have been proposed to lead to intellectual disability in DS, assess the extent to which data from studies using iPSC models supports these hypotheses, and identify current gaps in the field.

Fig. 1 |. Summary of cytoarchitectural differences in Down syndrome cortex relative to typical development.

A coronal section through the frontal lobe of a neonatal human brain. Fetuses and infants with Down syndrome (DS) exhibit gross anatomical deficits in brain structure, including lower whole-brain volume, thinner cortex, and reduced gyral and sulcal complexity^,,,–. Arrowheads indicate shallower, less complex sulci. Such differences reflect disruptions to the cellular processes that guide brain formation (insets). Specifically, the production and differentiation of neurons and astrocytes are disrupted during neurodevelopment in DS, resulting in fewer neurons and a greater proportion of astrocytes relative to neurons^,,,,,. Myelin deficiencies and disruption of oligodendrocyte production are also key features of DS neurodevelopment. Upward and downward arrows indicate increases or decreases in cell populations, respectively.

Fig. 2 |. Heterochrony in the developing Down syndrome cortex.

During typical early cortical development, neural progenitor cells (NPCs) undergo a period of expansion through multiple symmetrical divisions (top). At a certain point, NPCs begin to differentiate into neurons (neurogenesis), largely through a series of asymmetric divisions that produce one progenitor that will continue to proliferate and one terminally differentiated neuron. Over time, NPCs become gliogenic and produce astrocytes and oligodendrocytes. Evidence from human brain tissue and iPSC experiments suggests that a potential mechanism by which fewer neurons are produced in the Down syndrome (DS) brain is a relative shift in the timing of these events (heterochrony). Specifically, in DS neurodevelopment (bottom), evidence suggests that fewer NPCs are produced before the transition to neurogenesis, which ultimately sets the stage for the production of fewer neurons^,,–,,,. Second, it has been hypothesized that there is a premature transition from the neurogenic to the gliogenic stages, expanding the window of time for glial production and resulting in a larger proportion of glial cells (particularly astrocytes) relative to neurons^,,,,–.

Fig. 3 |. Synaptic landscape of the developing Down syndrome brain.

a, Dendritic spine distribution along cortical pyramidal neurons in the fetal and infant brain based on prior work using Golgi staining. During fetal development (left panel), there is relatively little difference in dendritic spine number or morphology. Cortical neurons in both typically developing and Down syndrome (DS) brains have similar numbers of long filipodia-like spines^–. However, neurons in the brains of neonates with DS have longer apical dendrites^–,. Infants with DS have fewer dendritic spines along cortical neurons, and the spines exhibit abnormal morphology, such as exceptionally long or short spines (right panel)^–. Cortical neurons from infants with DS also exhibit shorter apical dendrites, unlike those in the neonatal and fetal brain^–,. b, Synapse in an unaffected fetal brain and DS fetal brain. Synapses in the cortex of fetuses with DS have a smaller post-synaptic density and reduced expression of pre-synaptic proteins^–,. There is also reduced capacity for synaptic plasticity in trisomy 21 (T21) neurons. Evidence from stem cell-derived neurons indicates that T21 neurons do not readily undergo long-term potentiation (LTP) or depression (LTD) when subjected to electrophysiological paradigms that induce these forms of plasticity in control neurons, as illustrated in the traces, created using data from .