title: Development and pharmacological modulation of embryonic stem cell-derived neuronal network activity.
abstract: Embryonic stem cells can be differentiated into neurons of diverse neurotransmitter-specific phenotypes. While the time course of functional progression of ES cell-derived neural precursors towards mature neurons has been described in detail on single-cell level, the temporal development and pharmacological modulation of ES cell-derived neuronal network activity have not been explored yet. Neuronal network activity can be assessed by the microelectrode array (MEA) technology that allows simultaneous monitoring of the electrical activity exhibited by entire populations of neurons over several weeks or months in vitro. We demonstrate here that ES cell-derived neural precursors cultured on MEAs for 5 to 6 weeks develop neuronal networks with oscillating and synchronous spike patterns via distinct states of activity and change electrophysiological characteristics even after 5 to 6 weeks in culture pointing towards late maturational processes. These processes were accompanied by an increasing density of presynaptic vesicles. Furthermore, we demonstrated that ES cell-derived network activity was sensitive to synaptically acting drugs indicating that pharmacologically susceptible neuronal networks were generated. Thus, the MEA technology represents a powerful tool to describe the temporal progression of stem cell-derived neural populations towards mature, functioning neuronal networks that can be applied to investigate pharmacologically active compounds.
authors.affiliation: Department of Neurology, University Hospital Düsseldorf, Heinrich-Heine University, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Illes
authors.forename: Wiebke
authors.initials: W
authors.lastname: Fleischer
authors.forename: Mario
authors.initials: M
authors.lastname: Siebler
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Marcel
authors.initials: M
authors.lastname: Dihné
mesh_terms: D000200:Action Potentials; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004594:Electrophysiology; D053595:Embryonic Stem Cells / Q000166:cytology*; D018756:GABA Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D008839:Microelectrodes; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009415:Nerve Net / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009991:Oscillometry; D013572:Synaptic Vesicles / Q000648:ultrastructure; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018756:GABA Antagonists; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate