In vivo modeling of human neuron dynamics and Down syndrome

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Title: In vivo modeling of human neuron dynamics and Down syndrome
Authors: Real, R
Peter, M
Trabalza, A
Khan, S
Smith, MA
Dopp, J
Barnes, SJ
Momoh, A
Strano, A
Volpi, E
Knott, G
Livesey, FJ
De Paola, V
Item Type: Journal Article
Abstract: INTRODUCTION Scientists are building detailed maps of the cellular composition in the human brain to learn about its development. In the human cortex, the largest area of the mammalian brain, neural circuits are formed through anatomical refinement, including axon and synaptic pruning, and the emergence of complex patterns of network activity during early fetal development. Cellular analyses in the human brain are restricted to postmortem material, which cannot reveal the process of development. Model organisms are, therefore, commonly used for studies of brain physiology, development, and pathogenesis, but the results from model organisms do not always translate to humans. RATIONALE Systems to model human neuron dynamics and their dysfunction in vivo are needed. While biopsy specimens and the generation of neurons from induced pluripotent stem cells (iPSCs) could provide the necessary human genetic background, two- and three-dimensional cultures lack factors that normally support neuronal development, including blood vessels, immune cells, and interaction with innervating neurons from other brain areas. On the basis of previous stem cell transplantation studies in mice, we reasoned that the physiological microenvironment of the adult mouse brain could support the growth of human cortical tissue grafts that had been generated from iPSC-derived neuronal progenitors. With human neurons implanted into the mouse brain, high-resolution, real-time in vivo monitoring of human neuron dynamics for periods of time spanning the range from subseconds to several months becomes feasible. RESULTS We found that transplanted human iPSC–derived neuronal progenitors consistently assembled into vascularized territories with complex cytoarchitecture, mimicking key features of the human fetal cortex, such as its large size and cell diversification. Single-cell-resolution intravital microscopy showed that human neuronal arbors were refined via branch-specific retraction, rather than degeneration. Human synaptic networks restructured over the course of 4 months, while maintaining balanced rates of synapse formation and elimination. Human functional neurons rapidly and consistently acquired oscillatory population activity, which persisted over the 5-month observation period. Lastly, we used cortical tissue grafts derived from the fibroblasts of two individuals with Down syndrome, caused by supernumerary chromosome 21. We found that neuronal synapses in cells derived from these individuals were overly stable and that oscillatory neural activity was reduced in these grafts, revealing in vivo cellular phenotypes not otherwise apparent. CONCLUSION By combining live imaging in a multistructured tissue environment in mice with a human-specific genetic background, we provide insights into the earliest stages of human axon, synaptic, and network activity development and uncover cellular phenotypes in Down syndrome. Our work provides an alternative experimental system that can be used to study other disorders affecting the developing human cortex.
Issue Date: 16-Nov-2018
Date of Acceptance: 26-Sep-2018
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science
Journal / Book Title: Science
Volume: 362
Issue: 6416
Copyright Statement: © 2018 The Authors. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science, Volume 362, 16/11/2018, DOI:
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MD Multidisciplinary
General Science & Technology
Publication Status: Published
Open Access location:
Article Number: eaau1810
Online Publication Date: 2018-10-11
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine

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