title: Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.
abstract: Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Maltese
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Martella
authors.forename: Graziella
authors.initials: G
authors.lastname: Madeo
authors.forename: Irene
authors.initials: I
authors.lastname: Fagiolo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tassone
authors.forename: Giulia
authors.initials: G
authors.lastname: Ponterio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciamanna
authors.forename: Pierre
authors.initials: P
authors.lastname: Burbaud
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Paola
authors.initials: P
authors.lastname: Bonsi
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
mesh_terms: D000818:Animals; D001703:Biophysics; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D013569:Synapses / Q000187:drug effects* / Q000235:genetics; D013788:Thalamus / Q000166:cytology
chemical_list: D018680:Cholinergic Antagonists; C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones
keywords: dystonia; muscarinic receptor antagonists; striatum; synaptic plasticity