Cortical inputs and GABA interneurons imbalance projection neurons in the striatum of parkinsonian rats
Cortical inputs and GABA interneurons imbalance projection neurons in the striatum of parkinsonian rats
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DOI：
10.1523/jneurosci.4439-05.2006
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发表时间：
2006-04-05
影响因子：
5.3
通讯作者：
Gonon, F
中科院分区：
文献类型：
--
作者：
Mallet, N;Ballion, B;Gonon, F
纹状体接受大量皮层兴奋性输入，并被多巴胺密集支配。纹状体投射神经元可形成直接或间接通路。帕金森氏病的模型提出多巴胺能变性使这两种途径失衡，尽管缺乏直接的电生理证据。在这里，纹状体神经元通过电生理标准和神经生物素标记结合免疫组织化学或原位杂交鉴定。用6-羟多巴胺麻醉半帕金森大鼠，记录其体内自发放电活动和对皮层刺激的尖峰反应。我们发现，多巴胺能损伤使纹状体神经元（直接通路）受到抑制，而纹状体神经元（间接通路）被激活。我们还发现，在反向刺激下，皮质纹状体神经元优先支配纹状体或纹状顶神经元，并表明多巴胺能耗竭选择性地降低了前者的自发活动。因此，多巴胺退化引起了一系列的不平衡，这些不平衡从基底神经节扩散出去，影响整个基底神经节-丘脑-皮层回路。快速尖峰GABA中间神经元对纹状体投射神经元提供了有效的前馈抑制。我们在这里展示了这些中间神经元缩小了投射神经元对皮层刺激反应的时间窗口。在多巴胺缺失的纹状体中，由于这些中间神经元的内在活性没有改变，它们的前馈抑制加剧了纹状体的不平衡。事实上，纹状体状神经元的诱发反应时间窗较窄，纹状体状神经元的诱发反应时间窗较宽。因此，在多巴胺能耗竭后，皮层输入和GABA中间神经元可能会使纹状体投射神经元失衡，并代表了两种新的非多巴胺能机制，可能是帕金森病病理生理的次要因素。
The striatum receives massive cortical excitatory inputs and is densely innervated by dopamine. Striatal projection neurons form either the direct or indirect pathways. Models of Parkinson's disease propose that dopaminergic degeneration imbalances both pathways, although direct electrophysiological evidence is lacking. Here, striatal neurons were identified by electrophysiological criteria and Neurobiotin labeling combined with either immunohistochemistry or in situ hybridization. Their spontaneous discharge activity and spike response to cortical stimulation were recorded in vivo in anesthetized rats rendered hemi-parkinsonian by 6-hydroxydopamine. We showed that striatonigral neurons (direct pathway) were inhibited whereas striatopallidal neurons (indirect pathway) were activated by dopaminergic lesion. We also identified, with antidromic stimulations, corticostriatal neurons that preferentially innervate striatonigral or striatopallidal neurons and showed that dopaminergic depletion selectively decreased the spontaneous activity of the former. Therefore, dopamine degeneration induces a cascade of imbalances that spread out of the basal ganglia and affect the whole basal ganglia-thalamo-cortical circuits.Fast-spiking GABA interneurons provide potent feedforward inhibition of striatal projection neurons. We showed here that these interneurons narrowed the time window of the responses of projection neurons to cortical stimulation. In the dopamine-depleted striatum, because the intrinsic activity of these interneurons was not altered, their feedforward inhibition worsened the striatal imbalance. Indeed, the time window of the evoked responses was narrower for striatonigral neurons and wider for striatopallidal neurons. Therefore, after dopaminergic depletion, cortical inputs and GABA interneurons might imbalance striatal projection neurons and represent two novel nondopaminergic mechanisms that might secondarily contribute to the pathophysiology of Parkinson's disease.