A Multi-Scale Computational Model of Excitotoxic Loss of Dopaminergic Cells in Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in substantia nigra pars compacta (SNc). Although the exact cause of cell death is not clear, the hypothesis that metabolic deficiency is a key factor has been gaining attention in recent years. In the present study, we investigated this hypothesis using a multi-scale computational model of the subsystem of the basal ganglia comprising the subthalamic nucleus (STN), globus pallidus externa (GPe), and SNc. The proposed model is a multiscale model in that interaction among the three nuclei are simulated using more abstract Izhikevich neuron models, while the molecular pathways involved in cell death of SNc neurons are simulated in terms of detailed chemical kinetics. Simulation results obtained from the proposed model showed that energy deficiencies occurring at cellular and network levels could precipitate the excitotoxic loss of SNc neurons in PD. At the subcellular level, the models show how calcium elevation leads to apoptosis of SNc neurons. The therapeutic effects of several neuroprotective interventions are also simulated in the model. From neuroprotective studies, it was clear that glutamate inhibition and apoptotic signal blocker therapies were able to halt the progression of SNc cell loss when compared to other therapeutic interventions, which only slowed down the progression of SNc cell loss.