Analysing schizophrenia risk variants in NRXN1 using functional and mature neuronal cultures from patient-derived iPS cells

 

Introduction There is a growing interest in psychiatry to connect causal genetic variants to neurobiological dysfunction. Genomic studies indicate that copy number variants (CNVs) are related to the development of schizophrenia. Schizophrenia is a complex psychiatric disorder that affects nearly 1% of the worldʼs population. We previously described deletions in neurexin 1 (NRXN1) to be associated with schizophrenia. Neurexins are neuronal adhesion molecules. Disruption of the NRXN1 leads affects properties of synapses and leads to the disruption of neuronal networks. Especially, deletions in αneurexin 1 are involved in altered neural connectivity.

Methods For further analysis of NRXN1-related disease mechanisms, we used an in vitro cell culture model based on human induced pluripotent stem cells (iPS cells). Human iPS cells have been obtained from schizophrenia patients carrying CNVs in NRXN1. Patient derived induced pluripotent stem cells and healthy control cells were differentiated into mature and functional cortical neurons.

Results The analysis focused on gene expression regulating signaling pathways, which are part of the NRXN1 network. We applied transcript and protein analysis for identifying alterations in the expression of synaptic proteins. We verified the presence of NRXN1 and its interaction partners in differentiated neurons. We found differently regulated NRXN1 interaction partners in iPS cells carrying the CNV in NRXN1.

Conclusion In summary, the provided in vitro models represent promising models for applications using screening platforms enabling the identification of potential therapeutic targets in schizophrenia.