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Front Neural Circuits. 2019 Feb 25;13:11. doi: 10.3389/fncir.2019.00011. eCollection 2019.

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

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Computational Neuroscience Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT-Madras, Chennai, India.
Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom.
Blue Brain Project, Brain and Mind Institute, EPFL, Geneva, Switzerland.


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.


Globus Pallidus externa; Izhikevich neuron model; Parkinson's disease; SubThalamic Nucleus; Substantia Nigra pars compacta; deep brain stimulation; excitotoxicity; metabolic disorders

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