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

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Accession:244384
"... 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."
Reference:
1 . 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. Front Neural Circuits 13:11 [PubMed]
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Model Information (Click on a link to find other models with that property)
Model Type: Realistic Network;
Brain Region(s)/Organism: Basal ganglia; Subthalamic Nucleus;
Cell Type(s): Abstract Izhikevich neuron;
Channel(s):
Gap Junctions:
Receptor(s): AMPA; Gaba; NMDA;
Gene(s):
Transmitter(s): Dopamine; Glutamate; Gaba;
Simulation Environment: MATLAB;
Model Concept(s): Deep brain stimulation; Parkinson's;
Implementer(s): Muddapu, Vignayanandam R. [vignan.0009 at gmail.com]; Chakravarthy, Srinivasa V. [schakra at iitm.ac.in];
Search NeuronDB for information about:  AMPA; NMDA; Gaba; Dopamine; Gaba; Glutamate;
%% Spiking Excitotoxicity Model (SEM)
%Script for running the simulation

%%
%Created on 2016
%@author: Vignayanandam R. Muddapu (CNS@IIT-Madras)

%References
%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. Front Neural Circuits 13:11
%Available at: https://www.frontiersin.org/articles/10.3389/fncir.2019.00011/abstract [Accessed February 25, 2019].

%%
clc;clear;close all;
tic
time=clock;curdate=time(3);curmonth=time(2); % Tracking time

dur=50000; % Duration of simulation in milliseconds

randinit=1; % 0-No random initializatiion, 1-Random initializatiion
nolat=1; % 0-Lateral connections off, 1-Lateral connections on
pd=1; % 0-PD condition on, 1-PD condition off
lstsn=1; % 0-STN-SNc connection off, 1-STN-SNc connection on

wsg=1; % Connection strength from STN to GPe
wgs=20; % Connection strength from GPe to STN

sthrsnc=10.6; % Stress thershold
sthrsnc1=deci2str(sthrsnc);

wstsn=1; % Connection strength from STN to SNc
wstsn1=deci2str(wstsn);

GPUon=0; % 0-GPU usage off, 1-GPU usage on

filename0=strcat('SEM_Wstsn',num2str(wstsn1),'_Sthr',num2str(sthrsnc1),'_',num2str(dur),'msec_',num2str(curdate),'_',num2str(curmonth));

if(GPUon==1)
    [snc_firings,stn_firings,gpe_firings,DA,srnd,simtime]=SEM_GPU(dur,filename0,randinit,nolat,pd,lstsn,wsg,wgs,sthrsnc,wstsn);
else
    [snc_firings,stn_firings,gpe_firings,DA,srnd,simtime]=SEM(dur,filename0,randinit,nolat,pd,lstsn,wsg,wgs,sthrsnc,wstsn);
end

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