Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors
Identifieur interne : 000048 ( France/Analysis ); précédent : 000047; suivant : 000049Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors
Auteurs : M. Maltese [Italie] ; G. Martella [Italie] ; G. Madeo [Italie] ; I. Fagiolo [Italie] ; A. Tassone [Italie] ; G. Ponterio [Italie] ; G. Sciamanna [Italie] ; P. Burbaud [France] ; P. J. Conn [États-Unis] ; P. Bonsi [Italie] ; A. Pisani [Italie]Source :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2014.
English descriptors
- KwdEn :
- Animals, Biophysics, Cholinergic Antagonists (pharmacology), Corpus Striatum (cytology), Electric Stimulation, Excitatory Postsynaptic Potentials (drug effects), In Vitro Techniques, Long-Term Potentiation (drug effects), Mice, Mice, Transgenic, Molecular Chaperones (genetics), Mutation (genetics), Neurons (drug effects), Patch-Clamp Techniques, Synapses (drug effects), Synapses (genetics), Thalamus (cytology).
- MESH :
- chemical , genetics : Molecular Chaperones.
- chemical , pharmacology : Cholinergic Antagonists.
- cytology : Corpus Striatum, Thalamus.
- drug effects : Excitatory Postsynaptic Potentials, Long-Term Potentiation, Neurons, Synapses.
- genetics : Mutation, Synapses.
- Animals, Biophysics, Electric Stimulation, In Vitro Techniques, Mice, Mice, Transgenic, Patch-Clamp Techniques.
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 non-selective antagonists 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 NMDA current recorded from striatal neurons.
Our study demonstrate 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.
Url:
DOI: 10.1002/mds.26009
PubMed: 25195914
PubMed Central: 4216601
Affiliations:
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PMC:4216601Le document en format XML
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Maltese</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Martella, G" sort="Martella, G" uniqKey="Martella G" first="G." last="Martella">G. Martella</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Madeo, G" sort="Madeo, G" uniqKey="Madeo G" first="G." last="Madeo">G. Madeo</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Fagiolo, I" sort="Fagiolo, I" uniqKey="Fagiolo I" first="I." last="Fagiolo">I. Fagiolo</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Tassone, A" sort="Tassone, A" uniqKey="Tassone A" first="A." last="Tassone">A. Tassone</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Ponterio, G" sort="Ponterio, G" uniqKey="Ponterio G" first="G." last="Ponterio">G. Ponterio</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Sciamanna, G" sort="Sciamanna, G" uniqKey="Sciamanna G" first="G." last="Sciamanna">G. Sciamanna</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Burbaud, P" sort="Burbaud, P" uniqKey="Burbaud P" first="P." last="Burbaud">P. Burbaud</name><affiliation wicri:level="1"><nlm:aff id="A3">Institut des Maladies Neurodégénératives, CNRS UMR5293, Université Victor Segalen, Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut des Maladies Neurodégénératives, CNRS UMR5293, Université Victor Segalen, Bordeaux</wicri:regionArea><placeName><settlement type="city">Bordeaux</settlement></placeName></affiliation></author><author><name sortKey="Conn, P J" sort="Conn, P J" uniqKey="Conn P" first="P. J." last="Conn">P. J. Conn</name><affiliation wicri:level="1"><nlm:aff id="A4">Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University</wicri:regionArea><wicri:noRegion>Vanderbilt University</wicri:noRegion></affiliation></author><author><name sortKey="Bonsi, P" sort="Bonsi, P" uniqKey="Bonsi P" first="P." last="Bonsi">P. Bonsi</name><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Pisani, A" sort="Pisani, A" uniqKey="Pisani A" first="A." last="Pisani">A. Pisani</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Systems Medicine, University of Rome “Tor Vergata”, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Systems Medicine, University of Rome “Tor Vergata”</wicri:regionArea><wicri:noRegion>University of Rome “Tor Vergata”</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">IRCCS Fondazione Santa Lucia, Rome, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>IRCCS Fondazione Santa Lucia, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Biophysics</term><term>Cholinergic Antagonists (pharmacology)</term><term>Corpus Striatum (cytology)</term><term>Electric Stimulation</term><term>Excitatory Postsynaptic Potentials (drug effects)</term><term>In Vitro Techniques</term><term>Long-Term Potentiation (drug effects)</term><term>Mice</term><term>Mice, Transgenic</term><term>Molecular Chaperones (genetics)</term><term>Mutation (genetics)</term><term>Neurons (drug effects)</term><term>Patch-Clamp Techniques</term><term>Synapses (drug effects)</term><term>Synapses (genetics)</term><term>Thalamus (cytology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Molecular Chaperones</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Cholinergic Antagonists</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Corpus Striatum</term><term>Thalamus</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Excitatory Postsynaptic Potentials</term><term>Long-Term Potentiation</term><term>Neurons</term><term>Synapses</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term><term>Synapses</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Biophysics</term><term>Electric Stimulation</term><term>In Vitro Techniques</term><term>Mice</term><term>Mice, Transgenic</term><term>Patch-Clamp Techniques</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title><p id="P1">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.</p></sec><sec id="S2"><title>Methods</title><p id="P2">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<sup>+/Δgag</sup>) mice heterozygous for ΔE-torsinA and their controls (Tor1a<sup>+/+</sup> mice).</p></sec><sec id="S3"><title>Results</title><p id="P3">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 M<sub>1</sub> antagonist, VU0255035. Tor1a<sup>+/Δgag</sup> 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 M<sub>1</sub>-preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the non-selective antagonists orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M<sub>1</sub> receptors was further demonstrated by their ability to counteract the M<sub>1</sub>-dependent potentiation of NMDA current recorded from striatal neurons.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">Our study demonstrate that selective M<sub>1</sub> 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.</p></sec></div></front></TEI><affiliations><list><country><li>France</li><li>Italie</li><li>États-Unis</li></country><region><li>Latium</li></region><settlement><li>Bordeaux</li><li>Rome</li></settlement></list><tree><country name="Italie"><noRegion><name sortKey="Maltese, M" sort="Maltese, M" uniqKey="Maltese M" first="M." last="Maltese">M. Maltese</name></noRegion><name sortKey="Bonsi, P" sort="Bonsi, P" uniqKey="Bonsi P" first="P." last="Bonsi">P. Bonsi</name><name sortKey="Fagiolo, I" sort="Fagiolo, I" uniqKey="Fagiolo I" first="I." last="Fagiolo">I. Fagiolo</name><name sortKey="Fagiolo, I" sort="Fagiolo, I" uniqKey="Fagiolo I" first="I." last="Fagiolo">I. Fagiolo</name><name sortKey="Madeo, G" sort="Madeo, G" uniqKey="Madeo G" first="G." last="Madeo">G. Madeo</name><name sortKey="Madeo, G" sort="Madeo, G" uniqKey="Madeo G" first="G." last="Madeo">G. Madeo</name><name sortKey="Maltese, M" sort="Maltese, M" uniqKey="Maltese M" first="M." last="Maltese">M. Maltese</name><name sortKey="Martella, G" sort="Martella, G" uniqKey="Martella G" first="G." last="Martella">G. Martella</name><name sortKey="Martella, G" sort="Martella, G" uniqKey="Martella G" first="G." last="Martella">G. Martella</name><name sortKey="Pisani, A" sort="Pisani, A" uniqKey="Pisani A" first="A." last="Pisani">A. Pisani</name><name sortKey="Pisani, A" sort="Pisani, A" uniqKey="Pisani A" first="A." last="Pisani">A. Pisani</name><name sortKey="Ponterio, G" sort="Ponterio, G" uniqKey="Ponterio G" first="G." last="Ponterio">G. Ponterio</name><name sortKey="Ponterio, G" sort="Ponterio, G" uniqKey="Ponterio G" first="G." last="Ponterio">G. Ponterio</name><name sortKey="Sciamanna, G" sort="Sciamanna, G" uniqKey="Sciamanna G" first="G." last="Sciamanna">G. Sciamanna</name><name sortKey="Sciamanna, G" sort="Sciamanna, G" uniqKey="Sciamanna G" first="G." last="Sciamanna">G. Sciamanna</name><name sortKey="Tassone, A" sort="Tassone, A" uniqKey="Tassone A" first="A." last="Tassone">A. Tassone</name><name sortKey="Tassone, A" sort="Tassone, A" uniqKey="Tassone A" first="A." last="Tassone">A. Tassone</name></country><country name="France"><noRegion><name sortKey="Burbaud, P" sort="Burbaud, P" uniqKey="Burbaud P" first="P." last="Burbaud">P. Burbaud</name></noRegion></country><country name="États-Unis"><noRegion><name sortKey="Conn, P J" sort="Conn, P J" uniqKey="Conn P" first="P. J." last="Conn">P. J. Conn</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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