Cholinergic Modulation of CA1 Pyramidal Cells via M1 Muscarinic Receptor Activation: A Computational Study at Physiological and Supraphysiological Levels

The hippocampus receives extensive cholinergic modulation from the basal forebrain, which has been shown to have a prominent role in attention, learning, and synaptic plasticity. Disruptions of this modulation have been linked to a variety of neural disorders including Alzheimer's Disease. Pyramidal cells of the CA1 region of the hippocampus express several cholinergic receptor types in different locations throughout the cells' morphology. Developing a computational model of these cells and their modulation provides a unique opportunity to explore how each receptor type alters the overall computational role of the cell. To this end we implemented a kinetic model of the most widely distributed receptor type, the M1 muscarinic receptor and examined its role on excitation of a compartmental model of a CA1 pyramidal cell. We demonstrate that the proposed model replicates the increased pyramidal cell excitability seen in experimental results. We then used the model to replicate the effect of organophosphates, a class of pesticides and chemical weapons, whose effects consist in inhibiting the hydrolysis of acetylcholine; we demonstrated the effect of increasing concentrations of acetylcholine on the pyramidal cell's excitability. The cell model we implemented and its associated modulation constitute a basis for exploring the effects of cholinergic modulation in a large scale network model of the hippocampus both under physiological and supraphysiological levels.