Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: Role of M1 muscarinic receptors

Marta Maltese, Giuseppina Martella, Graziella Madeo, Irene Fagiolo, Annalisa Tassone, Giulia Ponterio, Giuseppe Sciamanna, Pierre Burbaud, P. Jeffrey Conn, Paola Bonsi, Antonio Pisani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1655-1665
Number of pages11
JournalMovement Disorders
Volume29
Issue number13
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • Dystonia
  • Muscarinic receptor antagonists
  • Striatum
  • Synaptic plasticity

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Medicine(all)

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    Maltese, M., Martella, G., Madeo, G., Fagiolo, I., Tassone, A., Ponterio, G., Sciamanna, G., Burbaud, P., Conn, P. J., Bonsi, P., & Pisani, A. (2014). Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: Role of M1 muscarinic receptors. Movement Disorders, 29(13), 1655-1665. https://doi.org/10.1002/mds.26009