Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway

S. Wang, J.R. van Rhijn, I. Akkouh, N. Kogo, N. Maas, A. Bleeck, E. Lewerissa, K. Wu, C. Schoenmaker, S. Djurovic, H. van Bokhoven, T. Kleefstra, N. Nadif Kasri, D. Schubert
doi: https://doi.org/10.1101/2021.05.25.445613
S. Wang
1Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J.R. van Rhijn
1Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
I. Akkouh
2Department of Medical Genetics, Oslo University Hospital, Oslo (Norway)
3NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, (Norway)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N. Kogo
4Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
5Department of Biophysics, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N. Maas
1Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. Bleeck
1Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
E. Lewerissa
4Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
K. Wu
4Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. Schoenmaker
4Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Djurovic
2Department of Medical Genetics, Oslo University Hospital, Oslo (Norway)
6NORMENT, Department of Clinical Science, University of Bergen, Bergen, (Norway)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
H. van Bokhoven
1Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
4Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
T. Kleefstra
4Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N. Nadif Kasri
1Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
4Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
D. Schubert
1Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, Nijmegen (the Netherlands)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: d.schubert@donders.ru.nl
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, have been shown to cause a novel neurodevelopmental syndrome and increase the risk for schizophrenia. To study the effect of decreased SETD1A function in human cells, we generated excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/−). Our data show that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was mainly characterized by an overly synchronized network. In individual neurons, this network phenotype was reflected by increased somatodendritic complexity and elevated synaptic connectivity. We found that this network phenotype was driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling revealed perturbations in gene sets associated with schizophrenia, synaptic transmission and glutamatergic synaptic function. At the molecular level, we identified specific changes in the cAMP/PKA pathway pointing toward a hyperactive cAMP pathway in SETD1A+/− neurons. Finally, using pharmacological experiments targeting the cAMP pathway we were able to rescue the network deficits in SETD1A+/− cultures. In conclusion, our results illuminate key molecular, cellular and network abnormalities caused by SETD1A haploinsufficiency and demonstrate a direct link between SETD1A and the cAMP-dependent pathway in human neurons.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted May 25, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway
S. Wang, J.R. van Rhijn, I. Akkouh, N. Kogo, N. Maas, A. Bleeck, E. Lewerissa, K. Wu, C. Schoenmaker, S. Djurovic, H. van Bokhoven, T. Kleefstra, N. Nadif Kasri, D. Schubert
bioRxiv 2021.05.25.445613; doi: https://doi.org/10.1101/2021.05.25.445613
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway
S. Wang, J.R. van Rhijn, I. Akkouh, N. Kogo, N. Maas, A. Bleeck, E. Lewerissa, K. Wu, C. Schoenmaker, S. Djurovic, H. van Bokhoven, T. Kleefstra, N. Nadif Kasri, D. Schubert
bioRxiv 2021.05.25.445613; doi: https://doi.org/10.1101/2021.05.25.445613

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (3506)
  • Biochemistry (7348)
  • Bioengineering (5324)
  • Bioinformatics (20266)
  • Biophysics (10020)
  • Cancer Biology (7744)
  • Cell Biology (11306)
  • Clinical Trials (138)
  • Developmental Biology (6437)
  • Ecology (9954)
  • Epidemiology (2065)
  • Evolutionary Biology (13325)
  • Genetics (9361)
  • Genomics (12587)
  • Immunology (7702)
  • Microbiology (19027)
  • Molecular Biology (7444)
  • Neuroscience (41049)
  • Paleontology (300)
  • Pathology (1230)
  • Pharmacology and Toxicology (2138)
  • Physiology (3161)
  • Plant Biology (6861)
  • Scientific Communication and Education (1273)
  • Synthetic Biology (1897)
  • Systems Biology (5313)
  • Zoology (1089)