Imbalance of ionic conductances contributes to diverse symptoms of demyelination
Imbalance of ionic conductances contributes to diverse symptoms of demyelination
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DOI：
10.1073/pnas.1013798107
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发表时间：
2010-11-30
影响因子：
11.1
通讯作者：
Sejnowski, Terrence J.
中科院分区：
文献类型：
--
作者：
Coggan, Jay S.;Prescott, Steven A.;Sejnowski, Terrence J.
哺乳动物动作电位的快速轴突传导依赖于髓鞘绝缘。脱髓鞘可引起减缓、阻断、去髓鞘化或矛盾的过度尖峰，这是脱髓鞘疾病中观察到的症状的基础。这些症状的多样性和发生时间尚不清楚，通常是间歇性的，与疾病进展无关。我们使用Hodgkin-Huxley和简化的Morris-Lecar模型模拟脱髓鞘（和继发性重塑）对固有轴突兴奋性的影响。模拟和分析表明，一个简单的解释的广度的症状，并揭示了钠泄漏电导的比例，g（Na）/g（L），作为一个四向开关控制兴奋性模式，包括尖峰失败，单尖峰传输，后放电，自发尖峰。当该比率低于阈值时发生故障。后放电发生在g（Na）/g（L）刚好低于自发尖峰的阈值，需要一个缓慢的内向电流，允许两个稳定的吸引子状态，一个对应于静止，另一个重复尖峰。一个容易发生后放电的神经元可以正常发挥功能，除非它被切换到“病理性”吸引子状态;因此，尽管潜在的病理可能会通过膜电导的连续变化缓慢发展，但轴突兴奋性的不连续变化可能会发生并导致阵发性症状。我们的结论是紧张性和阵发性阳性症状以及阴性症状可能是脱髓鞘后不同程度的g（Na）和g（L）之间的失衡的结果。G（L）钾通道的KCNK家族可能是治疗脱髓鞘症状的新药的重要靶点。
Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin-Huxley and reduced Morris-Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g(Na)/g(L), acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g(Na)/g(L) just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its "pathological" attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g(Na) and g(L) after demyelination. The KCNK family of g(L) potassium channels may be an important target for new drugs to treat the symptoms of demyelination.