Assembly of functionally integrated human forebrain spheroids

• Type of Material: Article
• Authors: Fikri Birey, Emory University; Jimena Andersen, Stanford University; Christopher D. Makinson, Stanford University; Saiful Islam, Stanford University; Wu Wei, Stanford University; Nina Huber, Stanford University; H. Christina Fan, BD Genomics; Kimberly R. Cordes Metzler, BD Genomics; Georgia Panagiotakos, University of California San Francisco; Nicholas Thom, Stanford University; Nancy A. O'Rourke, Stanford University; Lars M. Steinmetz, Stanford University; Jonathan A. Bernstein, Stanford University; Joachim Hallmayer, Stanford University; John R. Huguenard, Stanford University; Sergiu P. Pasca, Stanford University
• Language: English
• Date: 2017-05-04
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017, Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nature22330
• Title of Journal or Parent Work: NATURE
• Volume: 545
• Issue: 7652
• Start Page: 54
• End Page: +
• Grant/Funding Information: This work was supported by grants from NIH/National Institute of Mental Health (NIMH) grants 1R01MH100900 and 1R01MH100900-02S1, NIMH BRAINS Award R01MH107800, the California Institute of Regenerative Medicine (CIRM), the MQ Fellow Award, the Donald E. and Delia B. Baxter Foundation Scholar Award, the Kwan Research Fund and Stanford Start-up Funds (to S.P.P.), Child Research Health Institute Postdoctoral Fellowship (CHRI) (to F.B. and to N.H.), Idun Berry Postdoctoral Fellowship (to J.A.) the Stanford Medicine Dean’s Fellowship (to F.B., J.A., N.H.), the American Epilepsy Society and Wishes for Elliott Foundation Fellowship (to C.D.M.), NIH 5P01HG00020526 (to L.M.S.), the UCSF Program for Breakthrough Biomedical Research, Sandler Foundation (G.P.)
• Keywords: Science & Technology - Other Topics; HUMAN NEURONS; IN-VITRO; MOUSE; PLURIPOTENT STEM-CELLS; GENE-EXPRESSION; TIMOTHY SYNDROME; INTERNEURON MIGRATION; CORTICAL INTERNEURONS; Science & Technology; RNA-SEQ; NEOCORTEX; Multidisciplinary Sciences

Abstract

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (Î 3-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome- A neurodevelopmental disorder that is caused by mutations in the CaV 1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.