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Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1 -mutant neurons

Pak, ChangHui, Danko, Tamas, Mirabella, Vincent R., Wang, Jinzhao, Liu, Yingfei, Vangipuram, Madhuri, Grieder, Sarah, Zhang, Xianglong, Ward, Thomas, Huang, Yu-Wen Alvin, Jin, Kang, Dexheimer, Philip, Bardes, Eric, Mitelpunkt, Alexis, Ma, Junyi, McLachlan, Michael, Moore, Jennifer C., Qu, Pingping, Purmann, Carolin, Dage, Jeffrey L., Swanson, Bradley J., Urban, Alexander E., Aronow, Bruce J., Pang, Zhiping P., Levinson, Douglas F., Wernig, Marius, Südhof, Thomas C.·2021·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2025598118

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Abstract

Significance: Heterozygous NRXN1 deletions predispose to schizophrenia and other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impair neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. In a multicenter effort to test the generality and robustness of this pivotal observation, we used, at two laboratories, independent analyses of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Schizophrenia patient-derived neurons with NRXN1 deletions exhibited the same major decrease in neurotransmitter release and an increase in CASK protein as engineered human neurons with NRXN1 deletions. Strikingly, engineered mouse Nrxn1 -deficient neurons derived by the same method displayed no such phenotype, suggesting a human-specific role for NRXN1 . Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons, enabling future drug discovery efforts.

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A Cross-lab, cross-platform validation analyzing human patient-derived NRXN1del neurons
A Cross-lab, cross-platform validation analyzing human patient-derived NRXN1del neuronsCC-BY-NC-ND · From the PDF
Figure 2 Dendritic outgrowth and synapse formation are not significantly altered in NRXN1 del neurons trans-differentiated from iPS cells derived from schizophrenia patients
Figure 2 Dendritic outgrowth and synapse formation are not significantly altered in NRXN1 del neurons trans-differentiated from iPS cells derived from schizophrenia patientsCC-BY-NC-ND · From the PDF
Figure 3 NRXN1 del neurons generated from schizophrenia patient-derived iPS cells exhibit no significant changes in intrinsic electrical properties
Figure 3 NRXN1 del neurons generated from schizophrenia patient-derived iPS cells exhibit no significant changes in intrinsic electrical propertiesCC-BY-NC-ND · From the PDF
Figure 4 NRXN1 del neurons trans-differentiated from schizophrenia patient-derived iPS cells exhibit a significant decrease in the frequency of spontaneous excitatory synaptic events
Figure 4 NRXN1 del neurons trans-differentiated from schizophrenia patient-derived iPS cells exhibit a significant decrease in the frequency of spontaneous excitatory synaptic eventsCC-BY-NC-ND · From the PDF
Figure 5 Evoked excitatory synaptic transmission is impaired in NRXN1 del neurons transdifferentiated from patient-derived iPS cells due to a decrease in release probability
Figure 5 Evoked excitatory synaptic transmission is impaired in NRXN1 del neurons transdifferentiated from patient-derived iPS cells due to a decrease in release probabilityCC-BY-NC-ND · From the PDF
Figure 6 Heterozygous deletion of human NRXN1 using a newly engineered conditionally mutant iPS cell line replicates the impairment in presynaptic release probability observed in NRXN1 del neurons trans-differentiated from schizophrenia patient-derived iPS cells
Figure 6 Heterozygous deletion of human NRXN1 using a newly engineered conditionally mutant iPS cell line replicates the impairment in presynaptic release probability observed in NRXN1 del neurons trans-differentiated from schizophrenia patient-derived iPS cellsCC-BY-NC-ND · From the PDF
Figure 7 Mouse Nrxn1 del neurons fail to replicate the impairment in presynaptic release probability of human NRXN1 del neurons
Figure 7 Mouse Nrxn1 del neurons fail to replicate the impairment in presynaptic release probability of human NRXN1 del neuronsCC-BY-NC-ND · From the PDF
Figure 8 CASK protein levels are up-regulated in NRXN1 del neurons generated from schizophrenia patient-derived iPS cells and from genetically engineered iPS cells
Figure 8 CASK protein levels are up-regulated in NRXN1 del neurons generated from schizophrenia patient-derived iPS cells and from genetically engineered iPS cellsCC-BY-NC-ND · From the PDF
Figure 9 RNAseq analyses comparing the transcriptomes of control iPS cells and of NRXN1 del and control neurons generated from patient-derived, control, and engineered conditional iPS cells reveal distinct patterns of differential gene expression
Figure 9 RNAseq analyses comparing the transcriptomes of control iPS cells and of NRXN1 del and control neurons generated from patient-derived, control, and engineered conditional iPS cells reveal distinct patterns of differential gene expressionCC-BY-NC-ND · From the PDF
Figure 10 Gene expression is dysregulated in NRXN1 del neurons trans-differentiated from schizophrenia patient-derived iPS cells
Figure 10 Gene expression is dysregulated in NRXN1 del neurons trans-differentiated from schizophrenia patient-derived iPS cellsCC-BY-NC-ND · From the PDF

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Citations

Cites

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Metadata

Authors
Pak, C., Danko, T., Mirabella, V. R., Wang, J., Liu, Y., Vangipuram, M., Grieder, S., Zhang, X., Ward, T., Huang, Y.-W. A., Jin, K., Dexheimer, P., Bardes, E., Mitelpunkt, A., Ma, J., McLachlan, M., Moore, J. C., Qu, P., Purmann, C., Dage, J. L., Swanson, B. J., Urban, A. E., Aronow, B. J., Pang, Z. P., Levinson, D. F., Wernig, M., & Südhof, T. C.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2021-05-25
Volume
118
Issue
22
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.2025598118
Cited by
84
References
17
Language
en
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 184 d)
Funders
HHS | NIH | National Institute of Mental Health (5U19MH104172, MH122519)

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