Conditional Ablation of Striatal Neuronal Types Containing Dopamine D2 Receptor Disturbs Coordination of Basal Ganglia Function
Conditional Ablation of Striatal Neuronal Types Containing Dopamine D2 Receptor Disturbs Coordination of Basal Ganglia Function
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DOI：
10.1523/jneurosci.23-27-09078.2003
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发表时间：
2003-10
期刊：
影响因子：
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通讯作者：
H. Sano;Y. Yasoshima;Natsuki Matsushita;T. Kaneko;K. Kohno;I. Pastan;Kazuto Kobayashi
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文献类型：
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作者：
H. Sano;Y. Yasoshima;Natsuki Matsushita;T. Kaneko;K. Kohno;I. Pastan;Kazuto Kobayashi
多巴胺 (DA) 通过纹状体中的各种神经元群发挥基底神经节回路的突触组织作用。我们通过使用免疫毒素介导的细胞靶向对含有 DA D2 受体 (D2R) 的纹状体神经元类型进行了条件消融。突变小鼠在 D2R 基因的控制下表达人白细胞介素 2 受体 α 亚基。突变体的纹状体内免疫毒素治疗消除了大部分纹状体苍白球中型多棘神经元和胆碱能中间神经元。这些神经元的消除导致自发运动过度活跃，并减少响应 DA 刺激的运动激活。这种消除还诱导苍白球 (GP) 中 GAD 基因表达的上调和丘脑底核 (STN) 中细胞色素氧化酶活性的下调，同时减弱了 DA 诱导的纹状体黑质神经元中立即早期基因 (IEG) 的表达。此外，胆碱能中间神经元的化学损伤不会改变自发运动，但会导致 DA 诱导的运动激活适度增强。这种行为的增强伴随着纹状体黑质神经元中 IEG 表达的增加。这些数据表明，纹状体苍白球神经元的消融通过调节 GP 和 STN 活性引起自发性过度活跃，并且消融至少部分通过纹状体黑质活动的减弱而不是胆碱能细胞病变的影响导致 DA 诱导的行为减少。我们提出了一种可能的模型，其中纹状体苍白球神经元通过基底神经节电路的协调，双重调节依赖于 DA 传输状态的运动行为。
Dopamine (DA) exerts synaptic organization of basal ganglia circuitry through a variety of neuronal populations in the striatum. We performed conditional ablation of striatal neuronal types containing DA D2 receptor (D2R) by using immunotoxin-mediated cell targeting. Mutant mice were generated that express the human interleukin-2 receptor α-subunit under the control of the D2R gene. Intrastriatal immunotoxin treatment of the mutants eliminated the majority of the striatopallidal medium spiny neurons and cholinergic interneurons. The elimination of these neurons caused hyperactivity of spontaneous movement and reduced motor activation in response to DA stimulation. The elimination also induced upregulation of GAD gene expression in the globus pallidus (GP) and downregulation of cytochrome oxidase activity in the subthalamic nucleus (STN), whereas it attenuated DA-induced expression of the immediate-early genes (IEGs) in the striatonigral neurons. In addition, chemical lesion of cholinergic interneurons did not alter spontaneous movement but caused a moderate enhancement in DA-induced motor activation. This enhancement of the behavior was accompanied by an increase in the IEG expression in the striatonigral neurons. These data suggest that ablation of the striatopallidal neurons causes spontaneous hyperactivity through modulation of the GP and STN activity and that the ablation leads to the reduction in DA-induced behavior at least partly through attenuation of the striatonigral activity as opposed to the influence of cholinergic cell lesion. We propose a possible model in which the striatopallidal neurons dually regulate motor behavior dependent on the state of DA transmission through coordination of the basal ganglia circuitry.