Mergenthal Adam, Bouteiller Jean-Marie C, Yu Gene J, Berger Theodore W
Biomedical Engineering Department, Center for Neural Engineering, University of Southern California, Los Angeles, CA, United States.
Front Comput Neurosci. 2020 Sep 4;14:75. doi: 10.3389/fncom.2020.00075. eCollection 2020.
Dysfunction in cholinergic modulation has been linked to a variety of cognitive disorders including Alzheimer's disease. The important role of this neurotransmitter has been explored in a variety of experiments, yet many questions remain unanswered about the contribution of cholinergic modulation to healthy hippocampal function. To address this question, we have developed a model of CA1 pyramidal neuron that takes into consideration muscarinic receptor activation in response to changes in extracellular concentration of acetylcholine and its effects on cellular excitability and downstream intracellular calcium dynamics. This model incorporates a variety of molecular agents to accurately simulate several processes heretofore ignored in computational modeling of CA1 pyramidal neurons. These processes include the inhibition of ionic channels by phospholipid depletion along with the release of calcium from intracellular stores (i.e., the endoplasmic reticulum). This paper describes the model and the methods used to calibrate its behavior to match experimental results. The result of this work is a compartmental model with calibrated mechanisms for simulating the intracellular calcium dynamics of CA1 pyramidal cells with a focus on those related to release from calcium stores in the endoplasmic reticulum. From this model we also make various predictions for how the inhibitory and excitatory responses to cholinergic modulation vary with agonist concentration. This model expands the capabilities of CA1 pyramidal cell models through the explicit modeling of molecular interactions involved in healthy cognitive function and disease. Through this expanded model we come closer to simulating these diseases and gaining the knowledge required to develop novel treatments.
胆碱能调节功能障碍与包括阿尔茨海默病在内的多种认知障碍有关。这种神经递质的重要作用已在各种实验中得到探索，但关于胆碱能调节对健康海马体功能的贡献仍有许多问题未得到解答。为了解决这个问题，我们开发了一种CA1锥体神经元模型，该模型考虑了毒蕈碱受体对细胞外乙酰胆碱浓度变化的激活反应及其对细胞兴奋性和下游细胞内钙动力学的影响。该模型纳入了多种分子因子，以准确模拟此前在CA1锥体神经元计算建模中被忽略的几个过程。这些过程包括磷脂耗竭对离子通道的抑制以及细胞内钙库（即内质网）释放钙。本文描述了该模型以及用于校准其行为以匹配实验结果的方法。这项工作的结果是一个具有校准机制的房室模型，用于模拟CA1锥体细胞的细胞内钙动力学，重点是与内质网钙库释放相关的动力学。基于这个模型，我们还对胆碱能调节的抑制性和兴奋性反应如何随激动剂浓度变化做出了各种预测。该模型通过对健康认知功能和疾病中涉及的分子相互作用进行显式建模，扩展了CA1锥体细胞模型的能力。通过这个扩展模型，我们更接近模拟这些疾病，并获得开发新疗法所需的知识。
