Characterization of Kleefstra syndrome neuronal networks on multi-electrode arrays and a drug screen on human induced pluripotent stem cells
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2017-07-01
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en
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Kleefstra syndrome (KS) has been associated with haploinsufficiency of the epigenetic gene Euchromatin histone methyltransferase 1 (EHMT1). Additional genes were found to cause Kleefstra syndrome when mutated (SWI/SNF related, matrix associated, actin dependent regulator of chromatin (SMARCB1); Myeloid/lymphoid or mixed-lineage leukemia protein (MLL3); Methyl-CpG binding domain protein 5 (MBD5)). A disrupted neuronal network activity pattern of EHMT1-deficient rat cortical cultures was previously found on multi-electrode arrays compared to control cultures during development. In this study we characterized the electrophysiological activity of EHMT1-, SMARCB1-, MLL3-, and MBD5-deficient rat cortical networks. Compared to control rat cortical networks, a higher random activity was found in all Kleefstra-gene-deficient cortical networks early in development, whereas later in development most neuronal networks seem to be hyperexcitable. Next to these similarities, each network has unique features in their activity patterns. In the second part of the study we used another model system for Kleefstra syndrome: cultures of human induced neurons, generated from induced pluripotent stem cells of one KS patient and one control individual. We ran a drug screen, by testing 29 epigenetic inhibitors on these cells. One of them, a histone demethylase inhibitor, was found to improve the activity pattern of Kleefstra-line-derived iNeuron networks into the direction of the activity pattern of healthy control cultures, so a dose-response curve for this drug was computed.
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Faculteit der Sociale Wetenschappen