Modelling a Genetic Risk for Schizophrenia in Human Induced Pluripotent Stem Cells (Ipscs): Phenotypic Differences in Patients with Mutations in Nde1

• Published in: European neuropsychopharmacology 2017, Vol.27, p.S509-S510
• Main Authors: Johnstone, Mandy, Vasistha, Navneet, Livesey, Matthew, Burr, Karen, Whalley, Heather, Clair, David St, Blackwood, Douglas, Wyllie, David, Lawrie, Stephen, Johnstone, Eve C., McIntosh, Andrew M., Chandran, Siddharthan
• Format: Article
• Language: English
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2016.09.618

Schizophrenia is a major psychiatric disorder with strong evidence of genetic risk factors. Large-scale studies have shown that architectural genomic variation, in the form of copy number variants (CNVs), accounts for a significant portion of schizophrenia risk, including both sporadic and familial CNVs – most relatively rare, but of moderate to high penetrance. CNVs associated with schizophrenia, specifically those occurring in the Disrupted in Schizophrenia 1 (DISC1)-interactor, Nuclear distribution factor E-homolog 1 gene (NDE1), are proposed to exert their effect by converging on glutamate signalling pathways regulating synaptic plasticity. We have tested this hypothesis by generating a platform of human iPSCs from patients with schizophrenia, and other neurodevelopmental disorders, who are known to have CNVs affecting NDE1. We have differentiated these iPSCs into neural precursors and neuronal cells in vitro and have undertaken comparative studies between mutant and control cell lines including proliferation of neural precursors, morphology of differentiated neurons, neuronal expression patterns, signalling pathways, and N-Methyl-D Aspartate receptor (NMDAR) subunit expression. In parallel we have also studied the effects of NDE1 on developmental pathways in ‘cerebral organoids’; a three-dimensional tissue culture of human iPSC that mimics early stages (several weeks) of human cortical development. Studying neurodevelopmental disorders in three-dimensional in vitro cultures can teach us fundamental aspects of the development of the human cortex, that are beyond reach in current animal model systems. Here we present our preliminary findings from these studies.