Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway
Shan Wang,
Jon-Ruben van Rhijn,
Ibrahim Akkouh,
Naoki Kogo,
Nadine Maas,
Anna Bleeck,
Irene Santisteban Ortiz,
Elly Lewerissa,
Ka Man Wu,
Chantal Schoenmaker,
Srdjan Djurovic,
Hans van Bokhoven,
Tjitske Kleefstra,
Nael Nadif Kasri,
Dirk Schubert
Affiliations
Shan Wang
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands
Jon-Ruben van Rhijn
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands
Ibrahim Akkouh
Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway; NORMENT, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Naoki Kogo
Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, the Netherlands; Department of Biophysics, Donders Institute for Brain Cognition and Behaviour, 6525 AJ Nijmegen, the Netherlands
Nadine Maas
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands
Anna Bleeck
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands
Irene Santisteban Ortiz
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands
Elly Lewerissa
Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, the Netherlands
Ka Man Wu
Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, the Netherlands
Chantal Schoenmaker
Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, the Netherlands
Srdjan Djurovic
Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
Hans van Bokhoven
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, the Netherlands
Tjitske Kleefstra
Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, the Netherlands
Nael Nadif Kasri
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, the Netherlands
Dirk Schubert
Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands; Corresponding author
Summary: Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/−). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A+/− neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A+/− cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.
