Cell-intrinsic effects of TorsinA(delta E) disrupt dopamine release in a mouse model of TOR1A dystonia

• Type of Material: Article
• Authors: Anthony M Downs, Emory University; Xueliang Fan, Emory University; Radhika F Kadakia, Emory University; Yuping Donsante, Emory University; HA Jinnah, Emory University; Ellen Hess, Emory University
• Language: English
• Date: 2021-05-03
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Authors. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2021.105369
• Title of Journal or Parent Work: NEUROBIOLOGY OF DISEASE
• Volume: 155
• Start Page: 105369
• End Page: 105369
• Grant/Funding Information: This work was supported by United States Department of Defense grants W81XWH-15-1-0545 and W81XWH-20-1-0446, United States National Institute of Health Grants F31 NS103363 and T32 GM008602, and Cure Dystonia Now.
• Keywords: Acetylcholine; ONSET TORSION DYSTONIA; DYSTONIA-ASSOCIATED PROTEIN; Cholinergic interneurons; Life Sciences & Biomedicine; Fast scan cyclic voltammetry; VENTRAL STRIATUM; TorsinA; DYT1; NUCLEAR-ENVELOPE; ENDOPLASMIC-RETICULUM STRESS; Science & Technology; Neurosciences; Neurosciences & Neurology; DELTA-E-TORSINA; MUTANT TORSINA; CHOLINERGIC INTERNEURONS; DYT1 DYSTONIA; GENE DYT1

Abstract

TOR1A-associated dystonia, otherwise known as DYT1 dystonia, is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/ΔE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+ signaling, D2 dopamine autoreceptor function and GABAB receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.