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

NEUROBIOLOGY OF DISEASE

卷:155

Article

Downs, Anthony M.¹  Fan, Xueliang¹  Kadakia, Radhika F.¹  Donsante, Yuping¹  Jinnah, H. A.^2,3,4  Hess, Ellen J.^1,2 

[1] Emory Univ, Sch Med, Dept Pharmacol & Chem Biol, 101 Woodruff Circle,WMB 6304, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Neurol, 101 Woodruff Circle,WMB 6304, Atlanta, GA 30322 USA

[3] Emory Univ, Sch Med, Dept Human Genet, 101 Woodruff Circle,WMB 6300, Atlanta, GA 30322 USA

[4] Emory Univ, Sch Med, Dept Pediat, 101 Woodruff Circle,WMB 6300, Atlanta, GA 30322 USA

关键词: Fast scan cyclic voltammetry;    DYT1;    Cholinergic interneurons;    Acetylcholine;    TorsinA;   

DOI  :  10.1016/j.nbd.2021.105369

来源: Elsevier

【 摘 要 】

TOR1A-associated dystonia, otherwise known as DYT1 dystonia, is an inherited dystonia caused by a three basepair deletion in the TOR1A gene (TOR1A Delta E). 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(dE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(dE) 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(dE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(dE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/dE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(dE) 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(dE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(dE) mutation within dopamine neurons.