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.
Autistic Disorder
Cell Line
Cell Movement
Cells, Cultured
Female
GABAergic Neurons
Glutamic Acid
Humans
Interneurons
Long QT Syndrome
Male
Models, Biological
Neurogenesis
Neurons
Pluripotent Stem Cells
Prosencephalon
Spheroids, Cellular
Synapses
Syndactyly