Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.
Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.
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DOI：
10.1523/jneurosci.3875-11.2011
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发表时间：
2011-11-02
期刊：
影响因子：
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通讯作者：
Kreitzer AC
中科院分区：
文献类型：
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作者：
Gittis AH;Leventhal DK;Fensterheim BA;Pettibone JR;Berke JD;Kreitzer AC
快速尖峰中间神经元（FSI）可以对纹状体输出施加强有力的控制，并且已经在患有抽动秽语综合征的人类患者和肌张力障碍的啮齿动物模型中观察到该细胞群体的缺陷。然而，纹状体FSI参与运动控制的直接实验测试从未进行过。我们采用了一种新的药理学方法来研究选择性FSI抑制小鼠纹状体的行为后果。IEM-1460是GluA 2缺乏AMPAR的抑制剂，选择性地阻断FSI的突触兴奋，但不阻断纹状体投射神经元的突触兴奋。将IEM-1460输注到感觉运动纹状体中降低了FSI的放电率，但没有降低其他细胞群的放电率，并引起了强烈的肌张力障碍样损伤。这些结果提供了直接的证据表明，功能减退的纹状体FSI可以产生运动异常，并建议他们可能代表了一个新的治疗靶点，用于治疗多动性运动障碍。
Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette Syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.