SIMULATION OF THE BURSTING ACTIVITY OF NEURON-R15 IN APLYSIA - ROLE OF IONIC CURRENTS, CALCIUM BALANCE, AND MODULATORY TRANSMITTERS
SIMULATION OF THE BURSTING ACTIVITY OF NEURON-R15 IN APLYSIA - ROLE OF IONIC CURRENTS, CALCIUM BALANCE, AND MODULATORY TRANSMITTERS
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DOI：
10.1152/jn.1991.66.6.2107
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发表时间：
1991-12-01
影响因子：
2.5
通讯作者：
BYRNE, JH
中科院分区：
文献类型：
--
作者：
CANAVIER, CC;CLARK, JW;BYRNE, JH
1.在失智症中的R15爆发神经元的等效电路模型已与流体室模型相结合，从而产生一个模型，该模型结合了已知存在于R15胞体中的大多数膜离子通道的描述，以及提供细胞上的Ca 2+平衡。电压激活、钙失活的Ca 2+电流（表示为慢内向电流I（SI））足以产生爆发活动，而不引起任何其他钙依赖性电流（如非特异性阳离子电流I（NS）或钙激活K+电流I（K，Ca））。此外，还可以模拟典型R15爆发的许多特征，如放电间隔的抛物线变化、去极化后电位（DAP）以及爆发过程中放电下冲的逐渐减少.通过分别表征两个不同的时域来分析R15的动态活性：与动作电位相关的快速动态和与持续数十秒的低振幅振荡相关的缓慢动态（“慢波”）。通过将Na+电导（g（Na）BAR）设置为零来隔离缓慢的动力学，然后通过使用减少到两个变量的方程系统来研究：细胞内Ca 2+浓度和膜电位。系统的不动点位于这两个变量的零倾线的交点处。然后对固定点进行稳定性分析，以确定给定的一组参数是否会产生慢波活动.如果简化模型预测了g（Na）BAR设置为零的给定参数集的慢波振荡，则在g（Na）BAR重置为其控制值的完整模型中观察到相同参数集的爆发活动。然而，对于某些组的参数与g（Na）BAR在其通常的值，完整的模型表现出爆发活动，因为一个缓慢的振荡所产生的激活I（NS）的动作电位。这种振荡是由快速和慢速动力学之间的相互作用引起的，这种相互作用是简化模型无法单独预测的，并且当g（Na）BAR随后被设置为零时也没有观察到。如果g（NSBAR）也被设置为零，则这种差异消失。该模型预测了在动态活动中实验观察到的一些转变，包括以下：1）由Na+通道阻断剂河豚毒素（TTX）诱导的从爆发模式到慢波活动的转变，2）由Na+-K+泵阻断剂胰蛋白酶诱导的从爆发模式到搏动模式的转变，以及3）从超极化模式通过突发模式到由外部电流注入产生的拍频模式的整个转变范围。该模型还模拟了调节剂5-羟色胺（5-HT）、多巴胺、FMRFamide（Phe-Met-Arg-Phe-amide）和产卵激素（ELH）以及第二信使鸟苷3 '，5'-环一磷酸（cGMP）的作用。这些药物调节I（SI）或异常整流电流（I（R））或两者。这两种电流的调制之间的关键区别是，只有I（SI）影响钙零倾和电位零倾。这种区别为降低I（SI）的矛盾效应提供了另一种机制。具体地说，根据固定点的新位置，I（SI）的降低可以使细胞过度增殖或诱导缓慢搏动
1. An equivalent circuit model of the R15 bursting neuron in Aplysia has been combined with a fluid compartment model, resulting in a model that incorporates descriptions of most of the membrane ion channels that are known to exist in the somata of R15, as well as providing a Ca2+ balance on the cell.2. A voltage-activated, calcium-inactivated Ca2+ current (denoted the slow inward current I(SI)) was sufficient to produce bursting activity without invoking any other calcium-dependent currents (such as a nonspecific cation current, I(NS), or a calcium-activated K+ current, I(K,Ca)). Furthermore, many characteristics of a typical R15 burst could be simulated, such as a parabolic variation in interspike interval, the depolarizing afterpotential (DAP), and the progressive decrease in the undershoots of spikes during a burst.3. The dynamic activity of R15 was analyzed by separately characterizing two different temporal domains: the fast dynamics associated with action potentials and the slow dynamics associated with low-amplitude oscillations lasting tens of seconds ("slow waves"). The slow dynamics were isolated by setting the Na+ conductance (g(Na)BAR) to zero and then studied by the use of a system of equations reduced to two variables: intracellular concentration of Ca2+ and membrane potential. The fixed point of the system was located at the intersection of the nullclines for these two variables. A stability analysis of the fixed point was then used to determine whether a given set of parameters would produce slow-wave activity.4. If the reduced model predicted slow-wave oscillations for a given set of parameters with g(Na)BAR set to zero, then bursting activity was observed for the same set of parameters in the full model with g(Na)BAR reset to its control value. However, for certain sets of parameters with g(Na)BAR at its usual value, the full model exhibited bursting activity because of a slow oscillation produced by the activation of I(NS) by action potentials. This oscillation resulted from an interaction between the fast and slow dynamics that the reduced model alone could not predict and was not observed when g(Na)BAR was subsequently set to zero. If g(NSBAR) was also set to zero, this discrepancy disappeared.5. This model predicted a number of experimentally observed transitions in the dynamic activity, including the following: 1) the transition from a bursting mode to slow-wave activity induced by the Na+ channel blocker tetrodotoxin (TTX), 2) the transition from a bursting to a beating mode induced by the Na+-K+ pump blocker oubain, and 3) the entire range of transitions from a hyperpolarized mode through bursting modes to a beating mode produced by external current injection.6. The model also simulated the effects of the modulatory agents serotonin (5-HT), dopamine, FMRFamide (Phe-Met-Arg-Phe-amide), and egg-laying hormone (ELH), and the second messenger guanosine 3',5'-cyclic monophosphate (cGMP). These agents modulate either I(SI) or the anomalous rectifier current (I(R)) or both. A critical distinction between the modulation of these two currents was that only I(SI) affected both the calcium nullcline and the potential nullcline. This distinction provided an alternative mechanism for the paradoxical effects of reducing I(SI). Specifically, depending on the new location of the fixed point, a reduction in I(SI) can either hyperpolarize the cell or induce slow beating