Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia

Clinical and experimental data indicate striatal cholinergic dysfunction in dystonia, a movement disorder typically resulting in twisted postures via abnormal muscle contraction. Three forms of isolated human dystonia result from mutations in the TOR1A (DYT1), THAP1 (DYT6), and GNAL (DYT25) genes. Experimental models carrying these mutations facilitate identification of possible shared cellular mechanisms. Recently, we reported elevated extracellular striatal acetylcholine by in vivo microdialysis and paradoxical excitation of cholinergic interneurons (ChIs) by dopamine D2 receptor (D2R) agonism using ex vivo slice electrophysiology in Dyt1(Delta GAG/+) mice. The paradoxical excitation was caused by overactive muscarinic receptors (mACh Rs), leading to a switch in D2R coupling from canonical G(i/o) to noncanonical beta-arrestin signaling. We sought to determine whether these mechanisms in Dyt1(Delta GAG/+) mice are shared with Thap1(C54)(Y/)(+) knock-in and Gnal(+/-) knock-out dystonia models and to determine the impact of sex. We found Thap1(C54)(Y/)(+) mice of both sexes have elevated extracellular striatal acetylcholine and D2R-induced paradoxical ChI excitation, which was reversed by mAChR inhibition. Elevated extracellular acetylcholine was absent in male and female Gnal(+/-) mice, but the paradoxical D2R-mediated ChI excitation was retained and only reversed by inhibition of adenosine A2ARs. The G(i/o)-preferring D2R agonist failed to increase ChI excitability, suggesting a possible switch in coupling of D2Rs to beta-arrestin, as seen previously in a DYT1 model. These data show that, whereas elevated extracellular acetylcholine levels are not always detected across these genetic models of human dystonia, the D2R-mediated paradoxical excitation of ChIs is shared and is caused by altered function of distinct G-protein-coupled receptors.