Biophysical modeling of pathological brain states (Sudhakar et al 2019)

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Accession:262233
"Traumatic brain injuries (TBI) lead to dramatic changes in the surviving brain tissue. Altered ion concentrations, coupled with changes in the expression of membrane-spanning proteins, create a post-TBI brain state that can lead to further neuronal loss caused by secondary excitotoxicity. Several GABA receptor agonists have been tested in the search for neuroprotection immediately after an injury, with paradoxical results. These drugs not only fail to offer neuroprotection, but can also slow down functional recovery after TBI. Here, using computational modeling, we provide a biophysical hypothesis to explain these observations. We show that the accumulation of intracellular chloride ions caused by a transient upregulation of Na+-K+-2Cl- (NKCC1) co-transporters as observed following TBI, causes GABA receptor agonists to lead to excitation and depolarization block, rather than the expected hyperpolarization. The likelihood of prolonged, excitotoxic depolarization block is further exacerbated by the extremely high levels of extracellular potassium seen after TBI. Our modeling results predict that the neuroprotective efficacy of GABA receptor agonists can be substantially enhanced when they are combined with NKCC1 co-transporter inhibitors. This suggests a rational, biophysically principled method for identifying drug combinations for neuroprotection after TBI."
Reference:
1 . Sudhakar SK, Choi TJ, Ahmed OJ (2019) Biophysical Modeling Suggests Optimal Drug Combinations for Improving the Efficacy of GABA Agonists after Traumatic Brain Injuries. J Neurotrauma 36:1632-1645 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Extracellular;
Brain Region(s)/Organism:
Cell Type(s):
Channel(s): NKCC1;
Gap Junctions:
Receptor(s): AMPA; GabaA;
Gene(s):
Transmitter(s): Gaba; Glutamate;
Simulation Environment:
Model Concept(s): Depolarization block;
Implementer(s): Sudhakar, Shyam Kumar [shyamk at umich.edu];
Search NeuronDB for information about:  GabaA; AMPA; NKCC1; Gaba; Glutamate;
This is the Readme for the model associated with the paper:

Sudhakar, S. K., Choi, T. J., & Ahmed, O. J. (2019). Biophysical Modeling Suggests Optimal Drug Combinations for Improving the Efficacy of GABA Agonists after Traumatic Brain Injuries. Journal of Neurotrauma, 36, 1–14. https://doi.org/10.1089/neu.2018.6065



File descriptions

PYR_template.hoc - Neuron template of Regular spiking (RS) neuron described in the paper

test_RS_fig_1a1.hoc - Test file to generate figure 1a (upper panel, current = 300 pA)
test_RS_fig_1a2.hoc - Test file to generate figure 1a (middle panel, current = 700 pA)
test_RS_fig_1a3.hoc - Test file to generate figure 1a (lower panel, current = 2700 pA)


How to run the model

Download all files to your computer and cd to the corresponding folder On the terminal, type "mknrndll (or nrnivmodl)" to complile the .mod files
If you need more help running NEURON on your platform please consult:
https://senselab.med.yale.edu/ModelDB/NEURON_DwnldGuide
Type "nrngui test_model_RS.hoc" or " nrngui test_model_LR.hoc" to run the model

For accurate results, use a dt of 0.025 ms.

In case of any questions, please send an email to shyamk@umich.edu

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