Model files for simulating the ERK signaling pathway during L_LTP induction in the hippocampus

ERK signaling pathway include:

1. Calcium:
   • Calcium activation of RasGRF followed by RasGTP production
   • CamKII modulation of SynGap followed by increase RasGTP and Rap1GTP lifetime
2. cAMP
   • cAMP activation of Epac activation followed Rap1GTP
   • PKA phorylation of Src family kinase leading to Rap1GTP production
   • Gβγ recruitment of Src family kinase followed by activation of RasGTP

Figure: Schematic representation of signaling pathways activating ERK

The repository contains several types of simulation files (in Experiment) and python scripts for analysis of output (in Analysis). All output files were first processed using nrdh5_analv2 in https://github.com/neurord/NeuroRDanal

Model_ERK-stimdxxx.xml contain the entire model specification, which combines Reaction file (Rxn_ERK_xxx.xml), Morphology file (Morph.xml), initial conditions file (IC_ERK_xxx.xml), output file (Out_ERK_xxx.xml) and stimulation (Stim_ERK_xxx.xml). To run simulations, use NeuroRDv3.2.4 (https://github.com/neurord/stochdiff/releases/tag/v3.2.4) as follows:

java -jar /path/to/neurord-3.2.4-all-deps.jar /path/to/Model_ERK-stimd_xxx.xml

Subfolders

1. Experiment/Initialization/:

   • To match the in vitro data on basal concentration, simulate the model for about an hour to obtain steady-state concentrations for all molecules
   • To copy basal quantities of molecules, run:

   ARGS="IC_filename,h5_filename ,sstart ssend" then execfile('path/to/file/UpdateIC_basal.py')

2. Experiment/simulation/:

   • Reaction files and Morphology files used in all simulation.
   • IC files used in all simulations except robustness: random and factor simulations (set of molecules was changed by + or - 10%)

3. Experiment/simulation/Single_pulse:simulation of single pathways and combination of pathways using single pulses of either different durations (same amplitude) or different amplitudes (same duration)

   • Model_ERK-stimd-xxx.xml and Stim_ERKxxx.xml for each pathway
   • In filename, C* indicate concentration, d* indicates duration

4. Experiment/simulation/LTP_train/: simulation of single pathways and combination of pathways using 4 train of 100 Hz with different inter-train intervals (L_LTP stimulation protocol)

   Model_ERK-stimd-xxx.xml and Stim_ERKxxx.xml for each pathway

5. Experiment/simulation/LFS_ISO_HFS/: Simulation of response to LTP protocols that use isoproteronol (ISO) plus electrical stimulation to release glutamate. Model_ERK-stimd-.xml and Stim_ERK_xxx.xml Only ISO+1 train and ISO+5 hz produce LTP

   • ISO
   • 1 train of 100 Hz
   • 3 min of 5 Hz
   • ISO+1 train
   • ISO+5 Hz

   cAMP and calcium inputs are derived from simulation of a published model (Jȩdrzejewska-Szmek, J., Luczak, V., Abel, T., Blackwell, K.T., 2017. β-adrenergic signaling broadly contributes to LTP induction. PLOS Computational Biology 13, e1005657.)

6. Experiment/simulation/Robustness/:simulation to ensure the robustness of results to variation in parameter values

   • Model_ERK-stimd-xxx.xml and Stim_ERK_xxx.xml and IC_ERK_xxx.xml (Experiment/simulation/Robustness/analysis) modify rate constants or molecule quantity to assess effect on ERK
   • The files in Experiment/simulation/Robustness/analysis were generated using robustness_anal.py which uses robustness_function.py

7. Experiment/Analysis/:

   python files for statistical analysis of robustness simulations and linearity