Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington's disease

Date

2021-05-11

Author

Paraskevopoulou, Foteini
Parvizi, Poorya
Senger, Gokce
Tunçbağ, Nurcan
Rosenmund, Christian
Yildirim, Ferah

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Transcriptional dysregulation in Huntington's disease (HD) causes functional deficits in striatal neurons. Here, we performed Patchsequencing (Patch-seq) in an in vitro HD model to investigate the effects of mutant Huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at the single-cell level and to provide a platform for screening for therapeutics for the disease.

Subject Keywords

Huntington's disease, Patch-seq, Single-cell RNA sequencing, Striatum, Synaptic function

URI

https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85105445344&origin=inward
https://hdl.handle.net/11511/90836

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

https://doi.org/10.1073/pnas.2020293118

Collections

Graduate School of Informatics, Article

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Citation Formats

F. Paraskevopoulou, P. Parvizi, G. Senger, N. Tunçbağ, C. Rosenmund, and F. Yildirim, “Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease,” Proceedings of the National Academy of Sciences of the United States of America, pp. 0–0, 2021, Accessed: 00, 2021. [Online]. Available: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85105445344&origin=inward.