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.