Human induced pluripotent stem cell derived neurons as a model for Williams-Beuren syndrome

Williams-Beuren Syndrome (WBS) is caused by the microdeletion of approximately 25 genes on chromosome 7q11.23, and is characterized by a spectrum of cognitive and behavioural features. We generated cortical neurons from a WBS individual and unaffected (WT) control by directed differentiation of induced pluripotent stem cells (iPSCs). Single cell mRNA analyses and immunostaining demonstrated very efficient production of differentiated cells expressing markers of mature neurons of mixed subtypes and from multiple cortical layers. We found that passive membrane properties were comparable in these WBS and WT neurons, but there was a profound alteration in action potentials, with significantly prolonged WBS repolarization times and a WBS deficit in voltage-activated K+ currents. Miniature excitatory synaptic currents were normal, indicating that unitary excitatory synaptic transmission was not altered. Gene expression profiling identified 136 negatively enriched gene sets in WBS compared to WT neurons. These genes are involved in synaptic transmission and assembly, cation transport, axon guidance and elastic fibre pathways, and some encode ion channels. Our findings provide insight into gene dysregulation and electrophysiological defects in WBS patient neurons. 6 week-old neurons were generated from one control WT iPSC lines and three WBS iPSC lines (A100, B100, I100). Three independent replicates were pooled together and spotted on one array each