Laboratory of Genetics, Gage Lab, Salk Institute for Biological Studies, La Jolla, California; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
Laboratory of Genetics, Gage Lab, Salk Institute for Biological Studies, La Jolla, California.
Biol Psychiatry. 2020 Jul 15;88(2):150-158. doi: 10.1016/j.biopsych.2020.01.020. Epub 2020 Feb 4.
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).
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.
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.
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.
我们最近报道了一种在双相情感障碍（BD）患者来源的颗粒细胞神经元中表现出的超兴奋性表型，以及一种仅在来自对锂治疗有反应的 BD 患者的 CA3 锥体海马神经元中出现的超兴奋性，而在来自对锂治疗无反应的 BD 患者的 CA3 锥体海马神经元中则没有。
在这里，我们使用了来自 4 名对照者、3 名对锂有反应的 BD 患者和 3 名对锂无反应的 BD 患者的神经元的电流测量值。我们根据我们的测量结果改变模拟的齿状回和 CA3 海马神经元的电导，得出 BD 神经元的数值模拟。
计算模拟的 BD 齿状回神经元具有与实验结果相似的超兴奋性表型。只有来自锂反应者患者的模拟 BD CA3 神经元才具有超兴奋性。有趣的是，我们的计算模型捕捉到了我们在重新检查实验结果时也观察到的来自非反应者患者的海马神经元内在的生理不稳定性。这种不稳定性是由钠离子电流急剧减少引起的，同时钾电流的幅度增加。这些基线改变导致非反应者 BD 海马神经元的兴奋性发生剧烈变化，只需对其钠离子电流进行微小改变，即可在超兴奋性和低兴奋性状态之间交替。
我们基于测量结果的 BD 海马神经元计算模型再现了超兴奋性和生理不稳定性的实验表型。我们假设生理不稳定性表型强烈导致 BD 患者的情感波动。
