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, cilt.118, sa.19, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 118 Sayı: 19
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1073/pnas.2020293118
  • Dergi Adı: Proceedings of the National Academy of Sciences of the United States of America
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Agricultural & Environmental Science Database, Animal Behavior Abstracts, Aquatic Science & Fisheries Abstracts (ASFA), Artic & Antarctic Regions, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EconLit, EMBASE, Food Science & Technology Abstracts, INSPEC, Linguistic Bibliography, MathSciNet, MEDLINE, Pollution Abstracts, Psycinfo, Public Affairs Index, Veterinary Science Database, zbMATH, DIALNET
  • Anahtar Kelimeler: Huntington's disease, single-cell RNA sequencing, Patch-seq, synaptic function, striatum, INTRANUCLEAR INCLUSIONS, MOUSE MODELS, EXPRESSION, MICE, ABNORMALITIES, PATHOGENESIS, DYSFUNCTION, ACTIVATION, SYNAPSES, TOXICITY
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

© 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.