Zhou Shang-Lin, Chu Hong-Yuan, Jin Guo-Zhang, Cui Jian-Min, Zhen Xue-Chu
1] Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharmacol Sin. 2014 Jun;35(6):738-51. doi: 10.1038/aps.2014.23. Epub 2014 May 26.
3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation.
Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na(+) channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability.
SKF83959 (50 μmol/L) shifted the inactivation curve of Na(+) current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 (examined with current injection at the soma) was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability (examined with current injection at the dendrite) was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency.
SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug's anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.
3-甲基-6-氯-7,8-二羟基-1-(3-甲基苯基)-2,3,4,5-四氢-1H-3-苯并氮杂卓（SKF83959）已被证明可影响海马锥体细胞中几种类型的电压依赖性通道。本研究的目的是确定SKF83959对单个通道类型的调节如何在直流注入或突触激活期间对CA1锥体细胞的整体兴奋性产生影响。
制备大鼠海马切片。使用全细胞记录检查CA1锥体细胞中电压依赖性Na(+)通道的动力学、神经元兴奋性和去极化阻滞。使用海马CA1锥体细胞的真实数学模型来模拟SKF83959对神经元兴奋性的影响。
SKF83959（50μmol/L）使CA1锥体细胞中Na(+)电流的失活曲线移位10.3mV，但对激活曲线无影响。我们模拟预测的SKF83959对被动膜特性的影响，包括输入电阻降低和静息电位去极化，与实验数据一致。模拟结果表明，仅当膜电位补偿到对照水平时，才观察到SKF83959使胞体兴奋性降低（通过在胞体注入电流进行检测），而即使不进行膜电位补偿，也发现树突兴奋性降低（通过在树突注入电流进行检测），这导致在胞体引发的动作电位数量减少。此外，SKF83959显著促进了CA1锥体细胞中的去极化阻滞。SKF83959降低了兴奋性突触后电位（EPSP）的时间总和，并且在生理上更相关的是，降低了突触驱动的放电频率。
尽管SKF83959导致膜电位去极化，但它降低了CA1锥体细胞的兴奋性。这些结果可能揭示了该药物抗帕金森病作用的部分机制，也可能表明SKF83959具有潜在的抗癫痫作用。
