Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Anouk Verboven (Donders series 546)

23 March 2022

Promotors: Prof. dr. P.A.C. 't Hoen, Dr. N. Nadif Kasri
Co-promotor: Dr. L.B.A. de Vries

Transcriptomic and functional phenotyping of human neurons: towards a therapy for Koolen-de Vries Syndrome

Neurodevelopmental disorders are a group of conditions that result from impaired brain development. The underlying disease mechanisms often remain unknown, as it is challenging to study brain development in a human context. This research presents the application of novel phenotyping and drug screening approaches for neurodevelopmental disorders, with a primary focus on Koolen-de Vries Syndrome, a rare intellectual disability syndrome. To study human brain development in vitro, neurons were generated from human induced pluripotent stem cells (hiPSCs), derived from patients and healthy controls. The MEA-seq approach was used to combine transcriptomic and functional characterization of hiPSC-derived neurons, which resulted in identification of genes important for neuronal network function. In addition, a computational screen for candidate drug compound identification, using neuronal transcriptomic signatures as input, resulted in identification of three compounds that partly improved the neuronal network function of hiPSC-derived neurons derived from individuals with Koolen-de Vries Syndrome. The findings serve as a promising starting point for future studies to increase our understanding of mechanisms underlying neuronal network deficiencies in neurodevelopmental disorders, and provide a positive outlook on treatment development for KdVS in the future.