Cholinergic neuromodulation in hippocampal function and disease: From single-cell biophysics to network simulations

A fundamental mystery in neuroscience is how cellular components endow a particular anatomical region with a specific function. In the hippocampus, this function appears to be episodic memory. Here we examine how networks of pyramidal cells in the CA3 region, when regulated by cholinergic neuromodulation, theta- and gamma-frequency oscillations, and different classes of inhibitory interneurons can support memory function analogous to that of artificial attractor neural networks. This is a computational investigation of highly detailed, biophysical-level models of pyramidal cells and interneurons with a wide variety of intrinsic ion channels (Na, CaL, CaN, CaT, KDR, KM, KA, KAHP and KC ), connected in networks by AMPA-, NMDA- and GABAA-mediated synapses consistent with specific anatomy, physiology and pharmacology of CA3. At the level of single cells, the major findings are that the modulation of ion channels by increasing concentrations of acetylcholine (ACh) promotes a striking transition from bursting to regular spiking, increases the amplitude and speed of backpropagating action potentials, and decreases intracellular free calcium in the dendritic arbor. At the network level, we find that ACh regulates the frequency of the gamma oscillation in a concentration-dependent manner while its ability to alter the balance of AMPA- and NMDA-mediated synaptic currents can tune the network for optimal memory performance. The CA3 model is capable of robust autoassociative memory function and suggests putative roles for cholinergic neuromodulation, oscillations and interneurons in memory function. Cholinergic input is proposed to regulate the behavioral state of the network (bursting vs. spiking, learning vs. recall), the theta oscillation clocks inputs from entorhinal cortex, the gamma oscillation maintains rapid and temporally-precise coding of information, and different classes of interneurons generate gamma-band oscillations and balance the excitation of the pyramidal cell recurrent collaterals. Finally, simulations of cholinergic denervation and/or modulation by the amyloid β-peptide (Aβ) have implications for the cognitive decline that accompanies Alzheimer\u27s disease. Specifically, the observed slowing of the gamma oscillation is a novel and experimentally testable effect that his a significant impact on memory performance; the modulation of potassium channels by Aβ prevents the transition from a regular spiking to a bursting regime interfering with the switch between learning and recall