BACKGROUND We recently reported a hyperexcitability phenotype displayed in dentate gyrus granule neurons derived from patients with bipolar disorder (BD) as well as a hyperexcitability that appeared only in CA3 pyramidal hippocampal neurons that were derived from patients with BD who responded to lithium treatment (lithium responders) and not in CA3 pyramidal hippocampal neurons that were derived from patients with BD who did not respond to lithium (nonresponders). METHODS Here we used our measurements of currents in neurons derived from 4 control subjects, 3 patients with BD who were lithium responders, and 3 patients with BD who were nonresponders. We changed the conductances of simulated dentate gyrus and CA3 hippocampal neurons according to our measurements to derive a numerical simulation for BD neurons. RESULTS The computationally simulated BD dentate gyrus neurons had a hyperexcitability phenotype similar to the experimental results. Only the simulated BD CA3 neurons derived from lithium responder patients were hyperexcitable. Interestingly, our computational model captured a physiological instability intrinsic to hippocampal neurons that were derived from nonresponder patients that we also observed when re-examining our experimental results. This instability was caused by a drastic reduction in the sodium current, accompanied by an increase in the amplitude of several potassium currents. These baseline alterations caused nonresponder BD hippocampal neurons to drastically shift their excitability with small changes to their sodium currents, alternating between hyperexcitable and hypoexcitable states. CONCLUSIONS Our computational model of BD hippocampal neurons that was based on our measurements reproduced the experimental phenotypes of hyperexcitability and physiological instability. We hypothesize that the physiological instability phenotype strongly contributes to affective lability in patients with BD.

中文翻译：

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锂无反应性双相情感障碍患者的海马神经元表现出生理不稳定


背景我们最近报道了双相情感障碍（BD）患者的齿状回颗粒神经元中显示的过度兴奋表型，以及仅出现在对锂治疗有反应的BD患者的CA3锥体海马神经元中的过度兴奋（锂反应者） ），而不是来自对锂没有反应的 BD 患者（无反应者）的 CA3 锥体海马神经元。方法在这里，我们使用了对 4 名对照受试者、3 名对锂有反应的 BD 患者和 3 名无反应的 BD 患者的神经元电流的测量。我们根据测量结果改变了模拟齿状回和 CA3 海马神经元的电导，以得出 BD 神经元的数值模拟。结果计算模拟的 BD 齿状回神经元具有与实验结果相似的过度兴奋表型。只有来自锂反应患者的模拟 BD CA3 神经元是过度兴奋的。有趣的是，我们的计算模型捕捉到了海马神经元固有的生理不稳定性，这些神经元来自无反应患者，我们在重新检查实验结果时也观察到了这一点。这种不稳定性是由钠电流急剧减少引起的，同时伴随着几个钾电流幅度的增加。这些基线改变导致无反应者 BD 海马神经元的钠电流发生微小变化，从而大幅改变其兴奋性，在过度兴奋和低兴奋状态之间交替。 结论 我们的 BD 海马神经元计算模型基于我们的测量结果，再现了过度兴奋和生理不稳定的实验表型。我们假设生理不稳定表型对双相情感障碍患者的情感不稳定性有很大影响。