In vivo modeling of human neuron dynamics and Down syndrome

• Published in: Science (American Association for the Advancement of Science) 2018-11, Vol.362 (6416)
• Main Authors: Real, Raquel, Peter, Manuel, Trabalza, Antonio, Khan, Shabana, Smith, Mark A, Dopp, Joana, Barnes, Samuel J, Momoh, Ayiba, Strano, Alessio, Volpi, Emanuela, Knott, Graham, Livesey, Frederick J, De Paola, Vincenzo
• Format: Article
• Language: English
• Subjects: Animals; Axons - physiology; Axons - ultrastructure; Biopsy; Blood vessels; Brain; Brain architecture; Brain mapping; Cell size; Cerebral Cortex - blood supply; Cerebral Cortex - embryology; Cerebral Cortex - ultrastructure; Chromosome 21; Circuits; Cortex; Degeneration; Dendritic spines; Down syndrome; Down Syndrome - embryology; Down Syndrome - pathology; Down's syndrome; Dynamics; Fetuses; Fibroblasts; Gene mapping; Grafting; Grafts; Humans; Immune system; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - physiology; Induced Pluripotent Stem Cells - transplantation; Inhibitory postsynaptic potentials; Medical imaging; Mice; Mice, SCID; Microscopy, Fluorescence, Multiphoton; Mimicry; Modelling; Models, Biological; Networks; Neural networks; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - physiology; Neurodegeneration; Neurogenesis; Neuroglia - cytology; Neuroimaging; Neuronal Plasticity; Neuronal-glial interactions; Neurons; Neurons - pathology; Neurons - physiology; Neurons - ultrastructure; Oscillations; Pathogenesis; Phenotypes; Physiology; Pruning; Single-Cell Analysis; Skin & tissue grafts; Spine; Stem cells; Surgical implants; Synapses; Synapses - physiology; Synaptogenesis; Transplantation; Transplants; Transplants & implants
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aau1810

Harnessing the potential of human stem cells for modeling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. We show that human induced pluripotent stem cell (iPSC)-derived cortical neurons transplanted into the adult mouse cortex consistently organized into large (up to ~100 mm ) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; and oscillatory population activity mirrored the patterns of fetal neural networks. Lastly, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient-specific modeling of cortical development, physiology, and pathogenesis.