Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.
Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.
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DOI：
10.1371/journal.pone.0069984
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kuznetsov A
中科院分区：
文献类型：
--
作者：
Ha J;Kuznetsov A
多巴胺神经传递已被发现在成瘾行为中发挥作用，并在精神疾病中发生改变。多巴胺（DA）神经元显示两种功能不同的电生理活动模式：低频和高频放电。DA神经元的一个令人困惑的特征是其反应的以下组合：N-甲基-D-天冬氨酸受体（NMDAR）激活引起高频放电，而其他紧张性兴奋性刺激（-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯受体（AMPAR）激活或应用去极化）阻止放电。我们提出了一个新的计算模型，再现这种组合的反应，并解释最近的实验数据。也就是说，体细胞NMDAR刺激引起高频放电，并且比远端树突刺激更有效。我们进一步将模型简化为一个单室，并分析了NMDAR激活与其他刺激相比的不同高频反应的机制。标准的零倾分析表明，该机制是基于钙振荡的幅度的降低。分析证实，NMDAR的镁块提供的非线性电压依赖性决定了其提高点火频率的能力。我们进一步预测，电压依赖性的适度斜率在频率升高中起着核心作用。此外，我们提出了一个复极化电流，维持钙非依赖性的射击或射击的情况下，钙依赖性的复极化电流。我们预测，在DA神经元中观察到的ether-a-go-go电流（ERG）是最适合这一关键作用的。我们发现，一个钙依赖性和一个钙独立的振荡机制形成了一个连锁的负反馈回路的DA神经元的结构。该结构将DA神经元放电的研究与昼夜节律生物学联系起来，并确定了共同的最小模型，用于研究振荡的鲁棒性，这对两个系统的正常功能至关重要。
Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA) neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR) activation evokes high-frequency firing, whereas other tonic excitatory stimuli (-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR) activation or applied depolarization) block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether–a-go-go current (ERG), which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is critical for normal function of both systems.
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影响因子：
4.3
作者：
Drion G;Massotte L;Sepulchre R;Seutin V
通讯作者：
Seutin V
影响因子：
2.5
作者：
Canavier, C. C.;Landry, R. S.
通讯作者：
Landry, R. S.
影响因子：
2.9
作者：
Johnson, SW;Wu, YN
通讯作者：
Wu, YN
影响因子：
2.5
作者：
JURASKA, JM;WILSON, CJ;GROVES, PM
通讯作者：
GROVES, PM
DOI：
10.1523/jneurosci.2519-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Guzman JN;Sánchez-Padilla J;Chan CS;Surmeier DJ
通讯作者：
Surmeier DJ