Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors
Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors
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DOI：
10.1073/pnas.1009874107
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发表时间：
2010-08-17
影响因子：
11.1
通讯作者：
Greengard, Paul
中科院分区：
文献类型：
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作者：
Bateup, Helen S.;Santini, Emanuela;Greengard, Paul
基底神经节的直接和间接通路被认为可以相反地调节运动，并对病理行为产生不同的影响。然而，由于使用传统技术很难选择性地研究包含两条通路的神经元，因此分析每条通路对行为的独特贡献一直是一个挑战。在这里，我们提出了两种小鼠模型，其中纹状体黑质或纹状体苍白球神经元的功能由于纹状体信号蛋白多巴胺和 cAMP 调节的磷蛋白 Mr 32kDa (DARPP-32) 的细胞类型特异性删除而被选择性破坏。使用这些小鼠，我们发现纹状体黑质神经元中 DARPP-32 的缺失减少了基础运动和可卡因诱导的运动，并消除了帕金森病药物 L-DOPA 引起的运动障碍行为。相反，纹状体苍白球神经元中 DARPP-32 的缺失导致运动活性大幅增加，并显着降低抗精神病药物氟哌啶醇的强直反应。这些发现提供了对纹状体运动行为的直接和间接途径的选择性贡献的见解。
The direct and indirect pathways of the basal ganglia have been proposed to oppositely regulate locomotion and differentially contribute to pathological behaviors. Analysis of the distinct contributions of each pathway to behavior has been a challenge, however, due to the difficulty of selectively investigating the neurons comprising the two pathways using conventional techniques. Here we present two mouse models in which the function of striatonigral or striatopallidal neurons is selectively disrupted due to cell type-specific deletion of the striatal signaling protein dopamine-and cAMP-regulated phosphoprotein Mr 32kDa (DARPP-32). Using these mice, we found that the loss of DARPP-32 in striatonigral neurons decreased basal and cocaine-induced locomotion and abolished dyskinetic behaviors in response to the Parkinson's disease drug L-DOPA. Conversely, the loss of DARPP-32 in striatopallidal neurons produced a robust increase in locomotor activity and a strongly reduced cataleptic response to the antipsychotic drug haloperidol. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors.