Abstract:
:Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model.
journal_name
Elifejournal_title
eLifeauthors
Pappas SS,Darr K,Holley SM,Cepeda C,Mabrouk OS,Wong JM,LeWitt TM,Paudel R,Houlden H,Kennedy RT,Levine MS,Dauer WTdoi
10.7554/eLife.08352subject
Has Abstractpub_date
2015-06-08 00:00:00pages
e08352issn
2050-084Xjournal_volume
4pub_type
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