Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly.

Autor: Jansch C; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany., Ziegler GC; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany. ziegler_g@ukw.de.; Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany. ziegler_g@ukw.de., Forero A; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany., Gredy S; Institute of Physiology, Molecular Electrophysiology, University of Würzburg, Würzburg, Germany.; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia., Wäldchen S; Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany., Vitale MR; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia., Svirin E; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia., Zöller JEM; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.; Department of Translational Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands., Waider J; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany., Günther K; Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology and CMBI, Leopold-Franzens-University Innsbruck, Innsbruck, Austria.; Institute of Molecular Regenerative Medicine, SCI-TReCS, Paracelsus Medical University, Salzburg, Austria., Edenhofer F; Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology and CMBI, Leopold-Franzens-University Innsbruck, Innsbruck, Austria., Sauer M; Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany., Wischmeyer E; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.; Institute of Physiology, Molecular Electrophysiology, University of Würzburg, Würzburg, Germany., Lesch KP; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany. kplesch@mail.uni-wuerzburg.de.; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia. kplesch@mail.uni-wuerzburg.de.; Department of Translational Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands. kplesch@mail.uni-wuerzburg.de.
Jazyk: angličtina
Zdroj: Journal of neural transmission (Vienna, Austria : 1996) [J Neural Transm (Vienna)] 2021 Feb; Vol. 128 (2), pp. 225-241. Date of Electronic Publication: 2021 Feb 09.
DOI: 10.1007/s00702-021-02303-5
Abstrakt: Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.
Databáze: MEDLINE
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