Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.
Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.
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DOI：
10.1002/mds.26009
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发表时间：
2014-11
影响因子：
8.6
通讯作者：
Pisani, Antonio
中科院分区：
文献类型：
--
作者：
Maltese, Marta;Martella, Giuseppina;Madeo, Graziella;Fagiolo, Irene;Tassone, Annalisa;Ponterio, Giulia;Sciamanna, Giuseppe;Burbaud, Pierre;Conn, P. Jeffrey;Bonsi, Paola;Pisani, Antonio
广谱毒蕈碱受体拮抗剂代表了第一种可用于治疗不同运动障碍如肌张力障碍的药物。然而，这些药物的特异性及其作用机制尚不完全清楚。我们对抗胆碱能药物对DYT 1肌张力障碍基因敲入（Tor 1a +/Δgag）ΔE-torsinA杂合子小鼠及其对照（Tor 1a +/+小鼠）纹状体中型多棘神经元记录的短期和长期可塑性的影响进行了系统分析。拮抗剂的选择，以前被认为是选择性的毒蕈碱受体亚型，包括哌仑西平，trihexyphenydil，比哌立登，orphenadrine，和一种新的选择性M1拮抗剂，VU 0255035。Tor 1a +/Δgag小鼠皮质纹状体突触可塑性显著受损。抗胆碱能药物对纹状体神经元的内在膜特性和短期可塑性没有显着影响。然而，他们表现出不同的能力，以恢复皮质纹状体可塑性赤字。通过应用M1偏好拮抗剂哌仑西平和苯海索以及VU 0255035，获得了对长期抑郁（LTD）和突触去电位（SD）的完全拯救。相反，非选择性拮抗剂orphenadrine只产生了部分救援的突触可塑性，而比哌立登和ethopropazine未能恢复可塑性。M1受体的选择性进一步证明了他们的能力，以抵消M1-依赖的增强NMDA电流记录纹状体神经元。我们的研究表明，选择性M1毒蕈碱受体拮抗剂抵消突触可塑性缺陷在纹状体的DYT 1肌张力障碍突变的小鼠，提供了一个潜在的机制的理由，改善抗毒蕈碱治疗这种运动障碍的发展。
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.
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影响因子：
25
作者：
Ding, Jun;Guzman, Jaime N.;Surmeier, D. James
通讯作者：
Surmeier, D. James
影响因子：
8.6
作者：
Edwards, Mark J.;Huang, Ying-Zu;Bhatia, Kailash P.
通讯作者：
Bhatia, Kailash P.
影响因子：
4.7
作者：
Calabresi, P;Centonze, D;Bernardi, G
通讯作者：
Bernardi, G
影响因子：
14.5
作者：
Martella, Giuseppina;Tassone, Annalisa;Pisani, Antonio
通讯作者：
Pisani, Antonio
影响因子：
11.2
作者：
Ghilardi, MF;Carbon, M;Eidelberg, D
通讯作者：
Eidelberg, D