Xu Jun, Clancy Colleen E
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York, United States of America.
PLoS One. 2008 Apr 30;3(4):e2056. doi: 10.1371/journal.pone.0002056.
A critical property of some neurons is burst firing, which in the hippocampus plays a primary role in reliable transmission of electrical signals. However, bursting may also contribute to synchronization of electrical activity in networks of neurons, a hallmark of epilepsy. Understanding the ionic mechanisms of bursting in a single neuron, and how mutations associated with epilepsy modify these mechanisms, is an important building block for understanding the emergent network behaviors. We present a single-compartment model of a CA3 hippocampal pyramidal neuron based on recent experimental data. We then use the model to determine the roles of primary depolarizing currents in burst generation. The single compartment model incorporates accurate representations of sodium (Na(+)) channels (Na(V)1.1) and T-type calcium (Ca(2+)) channel subtypes (Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3). Our simulations predict the importance of Na(+) and T-type Ca(2+) channels in hippocampal pyramidal cell bursting and reveal the distinct contribution of each subtype to burst morphology. We also performed fast-slow analysis in a reduced comparable model, which shows that our model burst is generated as a result of the interaction of two slow variables, the T-type Ca(2+) channel activation gate and the Ca(2+)-dependent potassium (K(+)) channel activation gate. The model reproduces a range of experimentally observed phenomena including afterdepolarizing potentials, spike widening at the end of the burst, and rebound. Finally, we use the model to simulate the effects of two epilepsy-linked mutations: R1648H in Na(V)1.1 and C456S in Ca(V)3.2, both of which result in increased cellular excitability.
一些神经元的一个关键特性是爆发式放电，这在海马体中对电信号的可靠传递起着主要作用。然而，爆发式放电也可能促成神经元网络中电活动的同步，这是癫痫的一个标志。了解单个神经元爆发式放电的离子机制，以及与癫痫相关的突变如何改变这些机制，是理解涌现的网络行为的重要基石。我们基于最近的实验数据提出了一个CA3海马体锥体细胞的单室模型。然后我们使用该模型来确定主要去极化电流在爆发式放电产生中的作用。单室模型纳入了钠（Na(+)）通道（Na(V)1.1）和T型钙（Ca(2+)）通道亚型（Ca(V)3.1、Ca(V)3.2和Ca(V)3.3）的精确表征。我们的模拟预测了Na(+)和T型Ca(2+)通道在海马体锥体细胞爆发式放电中的重要性，并揭示了每种亚型对爆发形态的独特贡献。我们还在一个简化的可比模型中进行了快慢分析，结果表明我们模型中的爆发式放电是由两个慢变量相互作用产生的，即T型Ca(2+)通道激活门和Ca(2+)依赖性钾（K(+)）通道激活门。该模型再现了一系列实验观察到的现象，包括去极化后电位、爆发式放电末尾的峰电位展宽以及反弹。最后，我们使用该模型来模拟两种与癫痫相关的突变的影响：Na(V)1.1中的R1648H和Ca(V)3.2中的C456S，这两种突变都会导致细胞兴奋性增加。
