Excitotoxic loss of dopaminergic cells in PD (Muddapu et al 2019)

"... A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD (Parkinson's disease) therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc (Substantia Nigra pars compacta) 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."

Model Type: Realistic Network

Region(s) or Organism(s): Basal ganglia; Subthalamic Nucleus

Cell Type(s): Abstract Izhikevich neuron

Receptors: AMPA; Gaba; NMDA

Transmitters: Dopamine; Glutamate; Gaba

Model Concept(s): Deep brain stimulation; Parkinson's

Simulation Environment: MATLAB

Implementer(s): Muddapu, Vignayanandam R. [vignan.0009 at gmail.com]; Chakravarthy, Srinivasa V. [schakra at iitm.ac.in]


Muddapu VR, Mandali A, Chakravarthy VS, Ramaswamy S. (2019). A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity. Frontiers in neural circuits. 13 [PubMed]

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