Aging Decreases L-Type Calcium Channel Currents and Pacemaker Firing Fidelity in Substantia Nigra Dopamine Neurons
Aging Decreases L-Type Calcium Channel Currents and Pacemaker Firing Fidelity in Substantia Nigra Dopamine Neurons
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DOI：
10.1523/jneurosci.4228-13.2014
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发表时间：
2014-07-09
影响因子：
5.3
通讯作者：
Beckstead, Michael J.
中科院分区：
文献类型：
--
作者：
Branch, Sarah Y.;Sharma, Ramaswamy;Beckstead, Michael J.
黑质多巴胺神经元参与行为过程，包括认知，奖励学习和自愿运动。这些神经元的选择性退化是导致帕金森病（PD）相关运动缺陷的原因。衰老是帕金森病的主要危险因素，这表明正常衰老过程中多巴胺神经元发生的适应可能使个体易于发展为帕金森病。以前的研究表明，驱动自发的、有节奏的动作电位放电的独特的离子电导集可能使黑质多巴胺神经元易于发生选择性神经变性。在这里，我们表明，使用膜片钳电生理记录在脑切片，黑质多巴胺神经元从小鼠25 - 30个月的年龄（老）有可比的膜电容和输入电阻从小鼠2 - 7个月的年龄（年轻）的神经元。然而，与年轻小鼠的神经元相比，老年小鼠的神经元表现出更慢的放电速率，更窄的尖峰宽度和更可变的尖峰间期。来自老年小鼠的多巴胺神经元也表现出较小的L型钙通道电流，这提供了一种可能有助于冲动活动变化的合理机制。多巴胺神经元生理功能的减少可能导致在老年人群中观察到的随意运动和其他多巴胺介导的行为减少。此外，由于L型钙通道的药理学拮抗作用已被提出作为PD早期阶段的潜在治疗方法，因此我们的研究结果可能表明这种治疗干预的时间窗有限。
Substantia nigra dopamine neurons are involved in behavioral processes that include cognition, reward learning, and voluntary movement. Selective deterioration of these neurons is responsible for the motor deficits associated with Parkinson's disease (PD). Aging is the leading risk factor for PD, suggesting that adaptations occurring in dopamine neurons during normal aging may predispose individuals to the development of PD. Previous studies suggest that the unique set of ion conductances that drive spontaneous, rhythmic firing of action potentials could predispose substantia nigra dopamine neurons to selective neurodegen-eration. Here we show, using patch-clamp electrophysiological recordings in brain slices, that substantia nigra dopamine neurons from mice 25-30 months of age (old) have comparable membrane capacitance and input resistance to neurons from mice 2-7 months of age (young). However, neurons from old mice exhibit slower firing rates, narrower spike widths, and more variable interspike intervals compared with neurons from young mice. Dopamine neurons from old mice also exhibit smaller L-type calcium channel currents, providing a plausible mechanism that likely contributes to the changes in impulse activity. Age-related decrements in the physiological function of dopamine neurons could contribute to the decrease in voluntary movement and other dopamine-mediated behaviors observed in aging populations. Furthermore, as pharmacological antagonism of L-type calcium channels has been proposed as a potential treatment for the early stages of PD, our results could point to a limited temporal window of opportunity for this therapeutic intervention.