Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine
Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine
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DOI：
10.1093/brain/awp194
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发表时间：
2009-09-01
期刊：
影响因子：
14.5
通讯作者：
Pisani, Antonio
中科院分区：
文献类型：
--
作者：
Martella, Giuseppina;Tassone, Annalisa;Pisani, Antonio
DYT 1肌张力障碍是一种严重的遗传性肌张力障碍，其特征是不自主的扭转运动和异常姿势。它与dyt 1基因的缺失有关，导致蛋白质torsinA的突变形式。肌张力障碍的表现是不完全的，但是DYT 1突变的临床影响和非表现携带者都表现出运动学习受损和运动可塑性改变的证据。在这里，我们的特点是纹状体神经元突触可塑性的转基因小鼠表达正常人torsinA或其突变形式，与非转基因（NT）对照小鼠。中等多刺神经元记录NT和正常的人类torsinA小鼠表现出正常的长期抑郁症（LTD），而在突变的人类torsinA同窝仔LTD不能引起。此外，虽然长时程增强（LTP）可以诱导在所有的小鼠，它是更大的幅度在突变的人类torsinA小鼠。低频刺激（LFS）可以将增强的突触恢复到静息水平，这种现象称为突触去增强。LFS在NT和正常人torsinA小鼠中均诱导突触去增强（SD），但在突变人torsinA小鼠中不诱导。由于抗胆碱能药物是治疗人类肌张力障碍的有效药物治疗选择，我们推断内源性乙酰胆碱过量可能是突触可塑性损伤的基础。事实上，LTD和SD在突变的人torsinA小鼠中通过降低内源性乙酰胆碱水平或拮抗毒蕈碱M-1受体而被拯救。与正常人torsinA和NT同窝仔相比，突变人torsinA小鼠纹状体中乙酰胆碱酯酶活性显著增加，证实了乙酰胆碱张力增强的存在。此外，我们发现类似的改变，在毒蕈碱M-2/M-4受体基因敲除小鼠，其中增加纹状体乙酰胆碱水平已被记录的突触可塑性。一方面，LTD和SD的丧失，另一方面，LTP的增加，表明在DYT 1肌张力障碍模型中，抑制的丧失表征了突触可塑性的损害。更重要的是，我们的研究结果表明，不平衡的胆碱能传递在这些改变中起着关键作用，提供了一个线索，了解抗胆碱能药物恢复肌张力障碍的运动缺陷的能力。
DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M-1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M-2/M-4 receptor knockout mice, in which an increased striatal acetylcholine level has been documented. The loss of LTD and SD on one hand, and the increase in LTP on the other, demonstrate that a loss of inhibition characterizes the impairment of synaptic plasticity in this model of DYT1 dystonia. More importantly, our results indicate that an unbalanced cholinergic transmission plays a pivotal role in these alterations, providing a clue to understand the ability of anticholinergic agents to restore motor deficits in dystonia.