Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids.

Autor: Brady MV; Child Study Center, Yale University, New Haven, CT, 06520, USA., Mariani J; Child Study Center, Yale University, New Haven, CT, 06520, USA., Koca Y; Child Study Center, Yale University, New Haven, CT, 06520, USA., Szekely A; Department of Neurology, Yale University, New Haven, CT, 06520, USA., King RA; Child Study Center, Yale University, New Haven, CT, 06520, USA., Bloch MH; Child Study Center, Yale University, New Haven, CT, 06520, USA., Landeros-Weisenberger A; Child Study Center, Yale University, New Haven, CT, 06520, USA., Leckman JF; Child Study Center, Yale University, New Haven, CT, 06520, USA., Vaccarino FM; Child Study Center, Yale University, New Haven, CT, 06520, USA. flora.vaccarino@yale.edu.; Department of Neuroscience, Yale University, New Haven, CT, 06520, USA. flora.vaccarino@yale.edu.; Yale Stem Cell Center, Yale University, New Haven, CT, 06520, USA. flora.vaccarino@yale.edu.; Kavli Institute for Neuroscience at Yale, New Haven, CT, 06520, USA. flora.vaccarino@yale.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Dec; Vol. 27 (12), pp. 5007-5019. Date of Electronic Publication: 2022 Nov 29.
DOI: 10.1038/s41380-022-01880-5
Abstrakt: Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested an impaired medial ganglionic eminence fate and a decreased differentiation of cholinergic and GABAergic interneurons. Transcriptome analyses revealed organoid mispatterning in TS, with a preference for dorsolateral at the expense of ventromedial fates. Our results point to altered expression of GLI transcription factors downstream of the Sonic Hedgehog signaling pathway with cilia disruption at the earliest stages of BG organoid differentiation as a potential mechanism for the BG mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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