A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

Abstract

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). A full understanding of the underlying pathogenesis of this cell loss is unavailable, though a number of mechanisms have been indicated in the literature. A couple of these mechanisms, however, show potential for the development of radical and promising PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells by virtue of their excessive energy demands; the other is the excitotoxicity caused by excessive glutamate release onto SNc by an overactive Subthalamic Nucleus (STN). To investigate the latter hypothesis computationally, we developed a spiking neuron network model of the SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in a '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 that leads to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned PD mechanisms: metabolic vulnerability and glutamate excitotoxicity. Our simulation results show that the excitotoxic cause of SNc cell loss in PD might be initiated by weak excitotoxicity mediated by energy deficit, followed by strong excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies are simulated in the model to test their efficacy in slowing down or arresting SNc cell loss. Among the current therapeutics,

A review of computational modeling and deep brain stimulation: applications to Parkinson’s disease

“…Accordingly, the establishment of reliable computational models to investigate the inner events of the pathogenesis represents a key issue in the field. Current models of neuron and mean-field are predominantly biophysically based and account for several factors that influence the electrophysiology of neurons, such as processing of synaptic inputs, ionic basis of electrical excitability, and the effect of DA [12][13][14][15] . Here, we review the neuron model and mean-field neural model which are of physiological significance.…”

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

“…A more classic example is glutamatergic excitotoxicity imposed by the hyperactivity of the subthalamic nucleus (STN) and other subcortical nuclei induced by dopamine depletion . This concept offers additional possibilities to the decision about where to intervene with a putative disease‐modifying therapy, pointing our attention toward the STN as an appealing target …”

“…[47][48][49] This concept offers additional possibilities to the decision about where to intervene with a putative disease-modifying therapy, pointing our attention toward the STN as an appealing target. [49][50][51] Finally, the decision of how to treat is closely related to the decision of where to intervene. We will first discuss the disease-modifying potential of FUS subthalamotomy, a procedure that we are testing for symptomatic efficacy in clinical trials 8 (NCT03454425).…”

Influence of Energy Deficiency on the Molecular Processes ofSubstantia Nigra Pars CompactaCell for Understanding Parkinsonian Neurodegeneration: A Comprehensive Biophysical Computational Model

“…In an earlier computational study, we have shown that metabolic deficiency at the systems/network level can lead to neurodegeneration of SNc neurons due to excitotoxicity caused by an overexcited Subthalamic Nucleus (STN) (Muddapu et al, 2018(Muddapu et al, , 2019Muddapu and Chakravarthy, 2017). As a further step in understanding the PD pathophysiology, in the present study, we proposed to model the effects of metabolic deficiencies in SNc at subcellular level.…”

“…While existing treatments manage the symptoms of PDsometimes with miraculous effecta genuine cure demands an understanding of the root cause of SNc cell loss. Recently, a new approach towards PD etiologythat metabolic deficiencies at subcellular/cellular/network level can be a major cause of SNc cell loss in PDwas gaining attention (Bolam and Pissadaki, 2012;Muddapu et al, 2018Muddapu et al, , 2019Muddapu and Chakravarthy, 2017;Pacelli et al, 2015;Wellstead and Cloutier, 2011).…”