Desynchronization of Fast-Spiking Interneurons Reduces β-Band Oscillations and Imbalance in Firing in the Dopamine-Depleted Striatum
Desynchronization of Fast-Spiking Interneurons Reduces β-Band Oscillations and Imbalance in Firing in the Dopamine-Depleted Striatum
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DOI：
10.1523/jneurosci.3490-14.2015
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发表时间：
2015-01-21
影响因子：
5.3
通讯作者：
Blackwell, Kim T.
中科院分区：
文献类型：
--
作者：
Damodaran, Sriraman;Cressman, John R.;Blackwell, Kim T.
帕金森病期间基底神经节输出核中出现的β带（8- 30hz）振荡，以及直接和间接通路的不平衡激活，与该疾病相关的低运动运动输出有关。尽管多巴胺耗竭引起纹状体细胞和网络特性的改变，但尚不清楚在苍白球和网状黑质中测量到的异常活动是否是由纹状体异常活动引起的。本研究基于几种哺乳动物物种的数据，使用了一种中等棘神经元(msn)-快速尖峰中间神经元（FSIs）的计算网络模型，发现多巴胺消耗引起的细胞和电路特性的变化产生了稳健的β带振荡和不平衡放电。这些变化包括MSN之间的连接减少，FSI对D-2 MSN的抑制增加一倍，D-2 MSN树突兴奋性增加，D-2 MSN体细胞兴奋性降低。该模型显示，由于侧抑制减弱，MSN之间的去相关性降低，使得同步fsi对MSN的发射和振荡有很强的影响。侧抑制减弱也会增加MSN输出对皮层相关性的敏感性，这是一种与帕金森纹状体相关的情况。fsi的振荡反过来又被fsi之间通过间隙连接的快速电传输强烈调制。这些结果表明，使FSI活动不同步的药物可能为帕金森病的β -带振荡增强、不平衡放电和运动功能障碍提供一种新的治疗方法。
Oscillations in the beta-band (8-30 Hz) that emerge in the output nuclei of the basal ganglia during Parkinson's disease, along with an imbalanced activation of the direct and indirect pathways, have been linked to the hypokinetic motor output associated with the disease. Although dopamine depletion causes a change in cellular and network properties in the striatum, it is unclear whether abnormal activity measured in the globus pallidus and substantia nigra pars reticulata is caused by abnormal striatal activity. Here we use a computational network model of medium spiny neurons (MSNs)-fast-spiking interneurons (FSIs), based on data from several mammalian species, and find that robust beta-band oscillations and imbalanced firing emerge from implementation of changes to cellular and circuit properties caused by dopamine depletion. These changes include a reduction in connections between MSNs, a doubling of FSI inhibition to D-2 MSNs, an increase in D-2 MSN dendritic excitability, and a reduction in D-2 MSN somatic excitability. The model reveals that the reduced decorrelation between MSNs attributable to weakened lateral inhibition enables the strong influence of synchronous FSIs on MSN firing and oscillations. Weakened lateral inhibition also produces an increased sensitivity of MSN output to cortical correlation, a condition relevant to the parkinsonian striatum. The oscillations of FSIs, in turn, are strongly modulated by fast electrical transmission between FSIs through gap junctions. These results suggest that pharmaceuticals that desynchronize FSI activity may provide a novel treatment for the enhanced beta-band oscillations, imbalanced firing, and motor dysfunction in Parkinson's disease.