Dysregulated protocadherin-pathway activity as an intrinsic defect in iPSC-derived cortical interneurons from patients with schizophrenia

Shao, Zhicheng; Noh, Haneul; Kim, Woong Bin; Ni, Peiyan; Nguyen, Christine; Cote, Sarah E.; Noyes, Elizabeth; Zhao, Joyce; Parsons, Teagan; Park, James M; Zheng, Kelvin; Park, Joshua J.; Coyle, Joseph T.; Weinberger, Daniel R.; Straub, Richard E.; Berman, Karen F.; Apud, Jose A.; Ongur, Dost; Cohen, Bruce M; McPhie, Donna L.; Rapoport, Judith L.; Perlis, Roy H; Lanz, Thomas A.; Xi, Hualin Simon; Yin, Changhong; Huang, Weihua; Hirayama, Teruyoshi; Fukuda, Emi; Yagi, Takeshi; Ghosh, Sulagna; Eggan, Kevin C; Kim, Hae-Young; Eisenberg, Leonard M.; Moghadam, Alexander A; Stanton, Patric K.; Cho, Jun-Hyeong; Chung, Sangmi

doi:10.1038/s41593-018-0313-z

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Dysregulated protocadherin-pathway activity as an intrinsic defect in iPSC-derived cortical interneurons from patients with schizophrenia

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Author(s): Zhicheng Shao ¹ ^, ¹⁴ ^, ¹⁷ , Haneul Noh ¹ ^, ² ^, ¹⁷ , Woong Bin Kim ³ , Peiyan Ni ¹ ^, ² , Christine Nguyen ¹ , Sarah E. Cote ¹ , Elizabeth Noyes ¹ , Joyce Zhao ¹ , Teagan Parsons ¹ , James M. Park ² , Kelvin Zheng ² , Joshua J. Park ² , Joseph T. Coyle ¹ , Daniel R. Weinberger ⁴ , Richard E. Straub ⁴ , Karen F. Berman ⁵ , Jose Apud ⁵ , Dost Ongur ¹ , Bruce M. Cohen ¹ , Donna L. McPhie ¹ , Judith L. Rapoport ⁶ , Roy H. Perlis ⁷ , Thomas A. Lanz ⁸ , Hualin Simon Xi ⁹ , Changhong Yin ¹⁰ , Weihua Huang ¹⁰ , Teruyoshi Hirayama ¹¹ ^, ¹⁶ , Emi Fukuda ¹¹ , Takeshi Yagi ¹¹ , Sulagna Ghosh ¹² , Kevin C. Eggan ¹² , Hae-Young Kim ¹³ , Leonard M. Eisenberg ¹⁵ , Alexander A. Moghadam ² , Patric K. Stanton ² , Jun-Hyeong Cho ³ ^, ¹⁸ , Sangmi Chung ¹ ^, ² ^, ¹⁸

Publication date (Electronic): 21 January 2019

Journal: Nature neuroscience

Keywords: Schizophrenia, induced pluripotent stem cells, interneurons, protocadherin

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Abstract

We generated cortical interneurons (cINs) from iPSCs derived from14 healthy controls (HC cINs) and 14 patients with schizophrenia (SCZ cINs). Both HC cINs and SCZ cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, SCZ cINs had dysregulated expression of protocadherin genes, which lie within documented SCZ loci. Mice lacking protocadherin α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. SCZ cINs similarly showed defects in synaptic density and arborization, which were reversed by inhibitors of Protein Kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in SCZ cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

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Rapid single-step induction of functional neurons from human pluripotent stem cells.

Yingsha Zhang, Changhui Pak, Yan Han … (2013)

Available methods for differentiating human embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs) into neurons are often cumbersome, slow, and variable. Alternatively, human fibroblasts can be directly converted into induced neuronal (iN) cells. However, with present techniques conversion is inefficient, synapse formation is limited, and only small amounts of neurons can be generated. Here, we show that human ESCs and iPSCs can be converted into functional iN cells with nearly 100% yield and purity in less than 2 weeks by forced expression of a single transcription factor. The resulting ES-iN or iPS-iN cells exhibit quantitatively reproducible properties independent of the cell line of origin, form mature pre- and postsynaptic specializations, and integrate into existing synaptic networks when transplanted into mouse brain. As illustrated by selected examples, our approach enables large-scale studies of human neurons for questions such as analyses of human diseases, examination of human-specific genes, and drug screening. Copyright © 2013 Elsevier Inc. All rights reserved.

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Cortical inhibitory neurons and schizophrenia.

David A. Lewis, Takanori Hashimoto, David W Volk (2005)

Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.

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Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.

Juan E Belforte, Veronika Zsiros, Elyse R Sklar … (2010)

Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9809671

Journal ID (pubmed-jr-id): 21092

Journal ID (nlm-ta): Nat Neurosci

Journal ID (iso-abbrev): Nat. Neurosci.

Title: Nature neuroscience

ISSN (Print): 1097-6256

ISSN (Electronic): 1546-1726

Publication date Nihms-submitted: 24 January 2019

Publication date (Electronic): 21 January 2019

Publication date (Print): February 2019

Publication date PMC-release: 21 July 2019

Volume: 22

Issue: 2

Pages: 229-242

Affiliations

[1. ]Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA

[2. ]Department of Cell biology and Anatomy, New York Medical College, Valhalla, New York, USA

[3. ]Department of Molecular, Cell and Systems Biology, University of California, Riverside, Riverside, California, USA

[4. ]Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland, USA

[5. ]Clinical and Translational Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Intramural Research Program, Maryland, USA

[6. ]Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, USA

[7. ]Center for Quantitative Health, Massachusetts General Hospital, Boston, Massachusetts, USA

[8. ]Internal Medicine Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA

[9. ]Computational Sciences, Pfizer Inc., Cambridge, Massachusetts, USA

[10. ]Department of Pathology, New York Medical College, Valhalla, New York, USA

[11. ]KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Japan

[12. ]Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.

[13. ]Department of Public Health, New York Medical College, Valhalla, New York, USA.

[14. ]Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, Fujian, China

[15. ]New York Medical College/Westchester Medical Center Stem Cell Laboratory, Departments of Physiology and Medicine, New York Medical College, Valhalla, New York, USA

[16. ]Present address: Department of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical Science, Japan

[17. ]equal contributors

Author notes

Authors contributions:

Z.S., H.N., P.N., W.-B.K., J.T.C., R.H.S., B.M.C., T.H., E.F., T.Y., S.G., K.C.E., A.A.M., P.K.S., J.-H.C., and S.C. designed the experiments.

Z.S., H.N., P.N., C.N., S.E.C., E.N., J.Z., T.P., J.M.P., K.Z. and J.J.P. performed analysis of iPSC-derived interneurons. W.-B.K., A.A.M., P.K.S. and J.-H.C. performed electrophysiological studies. T.A.L., H.S.X., C.Y. and W.H. did RNAseq analysis. T.H., E.F. and T.Y. generated PCDHA KO mice and performed behavioral analysis of PCDHA KO mice. R.E.S., S.G. and K.C.E. performed genotype analysis. L.M.E performed confocal analysis. H.-Y.K. performed statistical analysis.

H.N., J.T.C., T.A.L., H.S.X., W.H., T.H., E.F., T.Y., S.G., K.C.E., A.A.M., P.K.S., J.-H.C., and S.C. wrote the manuscript.

D.R.W., R.E.S., K.F.B., J.A., D.O., B.M.C., D.L.M., J.L.R. and R.H.P. provided patient cell lines and reviewed data interpretation and manuscript contents.

T.H., T.Y., J.-H.C., and S.C. supported this study financially.

[18 ] Correspondence: schung8@ 123456nymc.edu , juncho@ 123456ucr.edu

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Manuscript ID: NIHMS1515514

DOI: 10.1038/s41593-018-0313-z

PMC ID: 6373728

PubMed ID: 30664768

SO-VID: 33275d00-9716-4a33-9e66-724b744b1f89

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Dysregulated protocadherin-pathway activity as an intrinsic defect in iPSC-derived cortical interneurons from patients with schizophrenia

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Abstract

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Most cited references 52

Rapid single-step induction of functional neurons from human pluripotent stem cells.

Cortical inhibitory neurons and schizophrenia.

Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.

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