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


Paraskevopoulou F., Parvizi P., Senger G., TUNÇBAĞ N. , Rosenmund C., Yildirim F.

Proceedings of the National Academy of Sciences of the United States of America, vol.118, no.19, 2021 (Journal Indexed in SCI Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 118 Issue: 19
  • Publication Date: 2021
  • Doi Number: 10.1073/pnas.2020293118
  • Title of Journal : Proceedings of the National Academy of Sciences of the United States of America

Abstract

© 2021 National Academy of Sciences. All rights reserved.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.