Ionic currents influencing spontaneous firing and pacemaker frequency in dopamine neurons of the ventrolateral periaqueductal gray and dorsal raphe nucleus (vlPAG/DRN): A voltage-clamp and computational modelling study
Ionic currents influencing spontaneous firing and pacemaker frequency in dopamine neurons of the ventrolateral periaqueductal gray and dorsal raphe nucleus (vlPAG/DRN): A voltage-clamp and computational modelling study
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DOI：
10.1007/s10827-017-0641-0
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发表时间：
2017-06-01
影响因子：
1.2
通讯作者：
Ungless，Mark A.
中科院分区：
文献类型：
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作者：
Dougalis，Antonios G.;Matthews，Gillian A. C.;Ungless，Mark A.
中脑导水管周围灰质腹外侧区(VlPAG)和中缝背核(DRN)的多巴胺(DA)神经元在体外以缓慢而规则的模式发出自发动作电位(AP)，但目前缺乏对其自发放电的内在膜特性的详细描述。为了解决这个问题，我们在脑片上进行了电压钳电生理研究，以描述它们的主要离子电流，然后构建了一个计算机模型，并使用模拟来理解硅胶中自动节律背后的机制。我们发现，在亚阈值范围内，vlPAG/DRN DA神经元表现出许多电压依赖性电流，包括超极化激活的阳离子电流(IH)、瞬时的A型钾电流(IA)、背景的持续性(INAP)钠电流和瞬时的低压激活(LVA)钙电流(ICaLVA)。脑片药理学与计算机模拟很好地一致，表明自发放电不依赖于IH、IA或钙电流。相反，当阻断钠电流时，自发放电停止，并在AP阈值以下获得稳定的、非振荡的膜电位。使用DA神经元模型，我们进一步表明，在峰间间期(ISI)复极过程中，钙电流表现出很小的激活(与钠电流相比)，而任何单独的钾电流，其阻断正向调制AP的放电频率，不是自发放电所必需的。相反，为了消除自律性，同时阻断一些钾电流是必要的。ISI过程中的复极最初是通过延迟整流钾电流的失活来调节的，而钠背景的“持续”电流通过驱动复极向AP阈值而对自律性是必不可少的。
Dopamine (DA) neurons of the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus (DRN) fire spontaneous action potentials (APs) at slow, regular patternsin vitrobut a detailed account of their intrinsic membrane properties responsible for spontaneous firing is currently lacking. To resolve this, we performed a voltage-clamp electrophysiological study in brain slices to describe their major ionic currents and then constructed a computer model and used simulations to understand the mechanisms behind autorhythmicityin silico. We found that vlPAG/DRN DA neurons exhibit a number of voltage-dependent currents activating in the subthreshold range including, a hyperpolarization-activated cation current (IH), a transient, A-type, potassium current (IA), a background, ‘persistent’ (INaP) sodium current and a transient, low voltage activated (LVA) calcium current (ICaLVA). Brain slice pharmacology, in good agreement with computer simulations, showed that spontaneous firing occurred independently of IH, IAor calcium currents. In contrast, when blocking sodium currents, spontaneous firing ceased and a stable, non-oscillating membrane potential below AP threshold was attained. Using the DA neuron model we further show that calcium currents exhibit little activation (compared to sodium) during the interspike interval (ISI) repolarization while, any individual potassium current alone, whose blockade positively modulated AP firing frequency, is not required for spontaneous firing. Instead, blockade of a number of potassium currents simultaneously is necessary to eliminate autorhythmicity. Repolarization during ISI is mediated initiallyviathe deactivation of the delayed rectifier potassium current, while a sodium background ‘persistent’ current is essentially indispensable for autorhythmicity by driving repolarization towards AP threshold.