A single-cell transcriptomic map of the human developing cortex in Down syndrome

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The human brain is a highly complex system comprised of billions of neurons interconnected to each other to form functional neural circuits. Normal brain function is dependent on effective communication between neurons, a process that requires the establishment of normal patterns of neural network activity. Several diseases that affect the brain result from impairments in the communication between neurons, which is why it is essential to understand how neural circuits are initially established and the mechanisms involved. We are particularly interested in understanding how the emergence of neural network activity can be controlled by the precise composition of various cell types in the immature foetal human brain and in Down syndrome (DS). DS is a common neurodevelopmental disorder and a major cause of congenital intellectual disability caused by a trisomy of Chromosome 21 (Ts21). Advances in our understanding of the underlying cellular and molecular mechanisms have been hampered by the limited availability of model systems that recapitulate this complex chromosomal condition. Cellular analyses in the immature human brain though focus on post-mortem fixed tissue samples, which cannot provide direct observation of dynamic events such the formation of electrical activity patterns. This limitation raises the question of how to study the cellular and molecular mechanisms of human neural circuit assembly and their dysfunction in DS. My team has recently developed a new approach to study in real-time the establishment of human neuronal networks using transplanted donor-derived induced pluripotent stem cells (iPSC) and longitudinal in vivo imaging. This experimental design allows the study of human neural network activity in a vascularized human graft over several weeks, overcoming several limitations of current in vitro approaches (e.g. the lack of blood vessels). We showed that neuronal activity is less synchronous in DS, which could contribute to cognitive deficits in DS. We also found a reduction in cortical volume and identified a potential molecular mechanism. With the prospect of developing strategies to correct defects in the wiring of the fetal brain in DS, we will obtain a map of all the cell types, which populate the developing DS cortex. This map will identify cortical cell populations which are either missing/reduced or whose maturation is delayed, which could explain the reduced size of the DS brain and its altered activity patterns. We will take advantage of powerful genetic tools that allow to probe the content of individual cells in the DS brain and in human cells transplanted in the brain of laboratory animals. The ultimate aim of this research proposal is therefore to gain new and fundamental insights into the cellular and molecular mechanisms that regulate the establishment of human cortical circuits, in the hope that this knowledge will, in the future, translate into new ways to rescue the network activity deficits in DS and guide the development of therapeutic strategies.