title: An anticholinergic reverses motor control and corticostriatal LTD deficits in Dyt1 ΔGAG knock-in mice.
abstract: DYT1 early-onset generalized torsion dystonia is an inherited movement disorder associated with mutations in DYT1 that codes for torsinA protein. The most common mutation seen in this gene is a trinucleotide deletion of GAG. We previously reported a motor control deficit on a beam-walking task in our Dyt1 ΔGAG knock-in heterozygous mice. In this report we show the reversal of this motor deficit with the anticholinergic trihexyphenidyl (THP), a drug commonly used to treat movement problems in dystonia patients. THP also restored the reduced corticostriatal long-term depression (LTD) observed in these mice. Corticostriatal LTD has long been known to be dependent on D2 receptor activation. In this mouse model, striatal D2 receptors were expressed at lower quantities in comparison to wild-type mice. Furthermore, the mice were also partially resistant to FPL64176, an agonist of L-type calcium channels that have been previously reported to cause severe dystonic-like symptoms in wild-type mice. Our findings collectively suggest that altered communication between cholinergic interneurons and medium spiny neurons is responsible for the LTD deficit and that this synaptic plasticity modification may be involved in the striatal motor control abnormalities in our mouse model of DYT1 dystonia.
authors: Department of Neurology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Mai T
authors: MT
authors: Dang
authors: Fumiaki
authors: F
authors: Yokoi
authors: Chad C
authors: CC
authors: Cheetham
authors: Jun
authors: J
authors: Lu
authors: Viet
authors: V
authors: Vo
authors: David M
authors: DM
authors: Lovinger
authors: Yuqing
authors: Y
authors: Li
mesh_terms: D000818:Animals; D002120:Calcium Channel Agonists; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004422:Dystonia Musculorum Deformans / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D055879:Gene Knock-In Techniques / Q000379:methods; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics* / Q000502:physiology*; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis; D014282:Trihexyphenidyl / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002120:Calcium Channel Agonists; C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; D018727:Muscarinic Antagonists; D011758:Pyrroles; D017448:Receptors, Dopamine D2; C071658:FPL 64176; D014282:Trihexyphenidyl