Hyperexcitable Substantia Nigra Dopamine Neurons in PINK1- and HtrA2/Omi-Deficient Mice
Hyperexcitable Substantia Nigra Dopamine Neurons in PINK1- and HtrA2/Omi-Deficient Mice
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DOI：
10.1152/jn.00466.2010
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发表时间：
2010-12-01
影响因子：
2.5
通讯作者：
Ungless, Mark A.
中科院分区：
文献类型：
--
作者：
Bishop, Matthew W.;Chakraborty, Subhojit;Ungless, Mark A.
Bishop MW，Chakraborty S，马修斯GA，Dougalis A，Wood NW，Feswear R，Ungless MA. PINK 1和HtrA 2/Omi缺陷小鼠黑质多巴胺神经元过度兴奋J Neurophysiol 104：3009-3020，2010.首次发表于2010年10月6日; doi：10.1152/jn.00466.2010。黑质多巴胺神经元的电生理特性可以影响其在帕金森病（PD）的基于毒素的模型中对变性的易感性，这表明在疾病的早期阶段可能参与兴奋毒性和/或活动减退机制。然而，尚不清楚SNC多巴胺神经元的电生理特性是否受到PD遗传易感性的影响。在这里，我们表明，PD相关基因，PINK 1或HtrA 2/Omi的删除，导致小电导钙激活钾通道的活性功能降低。这种减少导致SNC多巴胺神经元以不规则模式激发动作电位，并增强脑切片和体内的爆发性放电。相反，PINK 1缺失不影响腹侧被盖区多巴胺神经元或黑质网状部GABA能神经元的放电规律。这些研究结果表明，SNC多巴胺神经元兴奋性的变化可能在PD的选择性脆弱性中发挥作用。
Bishop MW, Chakraborty S, Matthews GA, Dougalis A, Wood NW, Festenstein R, Ungless MA. Hyperexcitable substantia nigra dopamine neurons in PINK1-and HtrA2/Omi-deficient mice. J Neurophysiol 104: 3009-3020, 2010. First published October 6, 2010; doi: 10.1152/jn.00466.2010. The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin-based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca2+-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD.