Abstract

Building Complex Neuronal Networks on Chips to Understand Neurodevelopmental Disorders

Nael Nadif Kasri, Professor Medical Neurosciences for Neurodevelopmental Disorders, Radboud University Medical Center Nijmegen

Recent progress in human genetics has led to the identification of hundreds of genes associated with neurodevelopmental disorders (NDDs). Despite considerable progress in elucidating the genetic architecture of NDDs, a major gap exists between the genetic findings and deciphering the pathophysiology of NDDs. Induced pluripotent stem cell technology allow us to generate all cell types present in the brain, in vitro, in a patient-specific manner. However, for most NDDs we currently do no know the exact cellular loci of disease, i.e. which cell type is contributing to the pathophysiology. In this talk I will explain our strategy to disentangle the cell type-specific contribution to neuronal network phenotypes in the context of NDDs. We generate composite cultures consisting of well-defined cell types differentiated on micro-electrode arrays (MEA) to probe for neuronal network activity during development. In addition, we combine MEA recordings with transcriptomics within the same experiment (MEA-Seq) to identify molecular pathways that underlie specific neuronal network phenotypes observed in ASD subtypes. Our data indicate that MEA-Seq is a robust and sensitive method to perform genotype-phenotype analyses, which can serve as a powerful platform to identify functional points of convergence between NDD genes and be used for high-throughput drug screening assays.