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Identification of neural oscillations and epileptiform changes in human brain organoids

Ranmal A. Samarasinghe, Osvaldo A. Miranda, Simon Mitchell, Isabella Ferando, Momoko Watanabe, Jessie E. Buth, Arinnae Kurdian, Peyman Golshani, Kathrin Plath, William E. Lowry, Jack M. Parent, Istvan Mody, View ORCID ProfileBennett G. Novitch
doi: https://doi.org/10.1101/820183
Ranmal A. Samarasinghe
1Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
2Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
4Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California USA
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Osvaldo A. Miranda
1Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
4Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California USA
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Simon Mitchell
5Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA
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Isabella Ferando
2Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Momoko Watanabe
1Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
4Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California USA
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Jessie E. Buth
1Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
4Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California USA
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Arinnae Kurdian
1Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
4Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California USA
6California State University, Northridge, Northridge, California USA
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Peyman Golshani
2Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
4Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California USA
7Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA
8West Los Angeles VA Medical Center, Los Angeles, California, USA
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Kathrin Plath
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
9Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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William E. Lowry
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
10Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA
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Jack M. Parent
11Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA
12Ann Arbor VA Healthcare System, University of Michigan Medical School, Ann Arbor, MI, USA
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Istvan Mody
2Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
13Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Bennett G. Novitch
1Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
4Intellectual Development and Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California USA
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  • ORCID record for Bennett G. Novitch
  • For correspondence: bnovitch@ucla.edu
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ABSTRACT

Human brain organoids represent a powerful tool for the study of human neurological diseases particularly those that impact brain growth and structure. However, many neurological diseases lack obvious anatomical abnormalities, yet significantly impact neural network functions, raising the question of whether organoids possess sufficient neural network architecture and complexity to model these conditions. Here, we explore the network level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex oscillatory network behaviors reminiscent of intact brain preparations. We further demonstrate strikingly abnormal epileptiform network activity in organoids derived from a Rett Syndrome patient despite only modest anatomical differences from isogenically matched controls, and rescue with an unconventional neuromodulatory drug Pifithrin-α. Together, these findings provide an essential foundation for the utilization of human brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

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Posted October 28, 2019.
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Identification of neural oscillations and epileptiform changes in human brain organoids
Ranmal A. Samarasinghe, Osvaldo A. Miranda, Simon Mitchell, Isabella Ferando, Momoko Watanabe, Jessie E. Buth, Arinnae Kurdian, Peyman Golshani, Kathrin Plath, William E. Lowry, Jack M. Parent, Istvan Mody, Bennett G. Novitch
bioRxiv 820183; doi: https://doi.org/10.1101/820183
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Identification of neural oscillations and epileptiform changes in human brain organoids
Ranmal A. Samarasinghe, Osvaldo A. Miranda, Simon Mitchell, Isabella Ferando, Momoko Watanabe, Jessie E. Buth, Arinnae Kurdian, Peyman Golshani, Kathrin Plath, William E. Lowry, Jack M. Parent, Istvan Mody, Bennett G. Novitch
bioRxiv 820183; doi: https://doi.org/10.1101/820183

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