Editors' ChoiceNeurodevelopment

Modeling human brain development

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Science Translational Medicine  07 Jun 2017:
Vol. 9, Issue 393, eaan4295
DOI: 10.1126/scitranslmed.aan4295

Abstract

Human forebrain spheroids enable in vitro observation of region-specific neural migration and circuit formation during brain development.

Well before birth, as a fetus is growing in the warmth and comfort of the womb, cells deep within its brain are migrating to different brain regions to form functional neural circuits. Gene mutations or environmental factors can alter this migratory process, and a growing body of research suggests that many neurological disorders are rooted in abnormal prenatal neural development. Pinpointing altered cellular and molecular processes in the developing brain could provide invaluable insights into these disorders, but studying developmental events in utero presents formidable challenges. Neural spheroids—three-dimensional organoids generated from human-induced pluripotent stem cells (iPS) —are a promising in vitro platform for modeling human brain development, but as yet, no one has been able to recapitulate interactions between different brain regions using spheroid models.

In a new study, Birey et al. assembled human forebrain spheroids in a dish and used them to study interneuron migration and integration. The researchers used human iPS cell lines derived from fibroblasts to create spheroids representing two different regions of the human forebrain—a cortical spheroid containing excitatory neurons and a deeper forebrain spheroid containing inhibitory neurons—and then fused the two spheroids. Inhibitory interneurons migrated from the deep forebrain spheroid into the cortical spheroid and successfully formed functional connections with the resident excitatory neurons. Live imaging of this model revealed cyclic migration patterns of the interneurons. This fused spheroid system-in-a-dish thus recapitulated the migration of fetal interneurons from the deep forebrain to the cortex and their subsequent maturation and integration into cortical circuits.

Next, the investigators generated human forebrain spheroids using cells from patients with Timothy syndrome, a severe neurodevelopmental disease characterized by autism spectrum disorder and epilepsy. Mutated calcium channels in these patients’ interneurons led to defective cyclic migration patterns: The cells moved forward more frequently but less efficiently, resulting in slower migration. When the fused patients’ spheroids were treated by chemicals that reduce the activity of the mutated calcium channels, the migration defect was rescued.

This study demonstrates the utility of this neural spheroid system as a tool for studying dynamic events in human fetal brain development. Assembling brain models in a dish will open up new windows into understanding the human brain and patient-specific disease mechanisms.

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