A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity.

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.