2024-11-0920210027-842410.1073/pnas.20202931182-s2.0-85105445344http://dx.doi.org/10.1073/pnas.2020293118https://hdl.handle.net/20.500.14288/9587Transcriptional dysregulation in Huntington's disease (HD) causes functional deficit s in striatal neurons. Here, we performed Patch-sequencing (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 deficit s 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.Multidisciplinary sciencesJournal Article1091-6490651329300003Q112471