A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity.

Vignayanandam Ravindernath Muddapu,Srikanth Ramaswamy,Alekhya Mandali,V Srinivasa Chakravarthy

doi:10.3389/fncir.2019.00011

Abstract

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). Although many mechanisms have been suggested, a decisive root cause of this cell loss is unknown. A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells compared to other dopaminergic clusters; the other is the SubThalamic Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter hypothesis computationally, we developed a spiking neuron network-model of SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in ‘stress' variable; when the stress in a SNc neuron exceeds a stress threshold, the neuron dies. The model shows that the interaction between SNc and STN involves a positive-feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway-effect, leading to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned mechanisms of SNc cell loss. Our simulation results show that the excitotoxic cause of SNc cell loss might initiate by weak-excitotoxicity mediated by energy deficit, followed by strong-excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies were simulated to test their efficacy in slowing down SNc cell loss. Among them, glutamate inhibition, dopamine restoration, subthalamotomy and deep brain stimulation showed superior neuroprotective-effects in the proposed model.

Highlights

There is a long tradition of investigation into the etiology and pathogenesis of Parkinson’s Disease (PD) that seeks to link molecular (Hwang, 2013; Ortiz et al, 2016; Chiti and Dobson, 2017; Anselmi et al, 2018; Stykel et al, 2018) and subcellular (Henchcliffe and Beal, 2008; Reeve et al, 2018; Tsai et al, 2018) factors with the disease development
The goal of this work was to develop a model which investigates the role of excitotoxicity in Substantia Nigra pars compacta (SNc) cell loss, where excitotoxicity was caused by SubThalamic Nucleus (STN) and precipitated by energy deficiency
The study suggests that excitotoxicity in SNc is initially driven by an energy deficit which leads to an initial dopamine reduction as a result of SNc cell loss

Summary

Introduction

There is a long tradition of investigation into the etiology and pathogenesis of Parkinson’s Disease (PD) that seeks to link molecular (pesticides, oxidative stress, protein dysfunction etc.) (Hwang, 2013; Ortiz et al, 2016; Chiti and Dobson, 2017; Anselmi et al, 2018; Stykel et al, 2018) and subcellular (mitochondrial dysfunction etc.) (Henchcliffe and Beal, 2008; Reeve et al, 2018; Tsai et al, 2018) factors with the disease development. Recent years see the emergence of two Excitotoxic Loss of Dopaminergic Cells in PD novel lines of investigation into PD pathogenesis. These approaches, that aim to understand the PD pathology at the cellular and network level, mark a significant deviation from the traditional approaches (Rodriguez et al, 1998; Pissadaki and Bolam, 2013; Pacelli et al, 2015; Chakravarthy and Moustafa, 2018). We have listed down some of the plausible factors which make SNc cells to be most susceptible

Objectives

Methods

Results

Conclusion