Assembly of functionally integrated human forebrain spheroids.
Fikri Birey, Jimena Andersen, Christopher D Makinson, Saiful Islam, Wu Wei, Nina Huber, H Christina Fan, Kimberly R Cordes Metzler, Georgia Panagiotakos, Nicholas Thom, Nancy A O'Rourke, Lars M Steinmetz, Jonathan A Bernstein, Joachim Hallmayer, John R Huguenard, Sergiu P Paşca
Author Information
Fikri Birey: Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Jimena Andersen: Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Christopher D Makinson: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
Saiful Islam: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Wu Wei: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Nina Huber: Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
H Christina Fan: BD Genomics, Menlo Park, California 94025, USA.
Kimberly R Cordes Metzler: BD Genomics, Menlo Park, California 94025, USA.
Georgia Panagiotakos: Department of Biochemistry and Biophysics, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA.
Nicholas Thom: Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Nancy A O'Rourke: Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Lars M Steinmetz: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Jonathan A Bernstein: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
Joachim Hallmayer: Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
John R Huguenard: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
Sergiu P Paşca: Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-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 Ca1.2 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.
