P3‐395: Reanimating basal forebrain cholinergic neurons in electrophysiology biosimulations using COPASI software

Alzheimer's disease (AD) is a devastating progressive brain disorder that leads to dementia and ultimately death. Basal forebrain cholinergic neurons are mainly affected in AD. Understanding cellular and network changes is key to create rational and effective new therapeutics to correct dysfunction and prevent neuronal damage. Due to the difficulties of obtaining recordings from control and AD patient brains, we propose a novel and patent-pending approach to reconstruct neurons and network function. A multi-compartmental model has been developed for rodent basal forebrain cholinergic neurons with established gene expression levels. Reconstruction of neurons and network function were acquired using the Transcriptome-To-Physiome™ NeurobioSimulation. Gene expression values [NCBI GEO GSE 13379] were used to derive protein level and kinetic parameters for ligand and voltage gated ion channels in the TTP™ NeurobioSimulator Model using COPASI software. Global parameters for membrane potential used permeability and ion concentrations inside and outside of the membrane in the Goldman-Hodgkin-Katz equation. Three compartments of the model neuron are included: glutamate synapse, distal dendrite, and proximal dendrite. The simulation of voltage-gated sodium channel activation and inactivated states of distal dendrites of cholinergic modeled neurons depends on the Excitatory Post Synaptic Potential (EPSP) event. This distally activated event yielded temporally relevant proximal dendritic activation and inactivation of voltage-gated sodium and potassium channels in the reconstructed neuron. Voltage-gated sodium channel open state duration, in the dendrites, could be modified by adjusting the k-value for transition to the inactivation state of the channel; whereas the concentration determined the peak amplitude. Simulated electrophysiological signatures exhibited similar temporal summation dynamics as those observed in the literature. Our current work demonstrates that electrophysiological reconstruction of basal forebrain cholinergic rodent neurons is not only feasible and reliable but time sensitive and cost effective making this novel methodology an effective approach towards developing therapeutics for neurodegenerative diseases. In future studies, we will reconstruct the electrophysiology of vulnerable neuronal populations in the AD brain and compare them to controls thus lending substantial insight into molecular and network function corollary to neuropathogenesis. Our novel approach will ascertain the roles of diverse genes in neuronal functions that are impaired in AD.