Multitarget pharmacology for Dystonia in M1 (Neymotin et al 2016)

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Accession:189154
" ... We developed a multiscale model of primary motor cortex, ranging from molecular, up to cellular, and network levels, containing 1715 compartmental model neurons with multiple ion channels and intracellular molecular dynamics. We wired the model based on electrophysiological data obtained from mouse motor cortex circuit mapping experiments. We used the model to reproduce patterns of heightened activity seen in dystonia by applying independent random variations in parameters to identify pathological parameter sets. ..."
Reference:
1 . Neymotin SA, Dura-Bernal S, Lakatos P, Sanger TD, Lytton WW (2016) Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex. Front Pharmacol 7:157 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Realistic Network; Molecular Network;
Brain Region(s)/Organism: Neocortex;
Cell Type(s): Neocortex V1 L6 pyramidal corticothalamic cell; Neocortex U1 L2/6 pyramidal intratelencephalic cell; Neocortex V1 interneuron basket PV cell; Neocortex fast spiking (FS) interneuron; Neocortex spiking regular (RS) neuron; Neocortex spiking low threshold (LTS) neuron; Neocortex layer 4 neuron; Neocortex layer 2-3 interneuron; Neocortex layer 4 interneuron; Neocortex layer 5 interneuron; Neocortex layer 6a interneuron;
Channel(s): I A; I h; I_SERCA; Ca pump; I K,Ca; I Calcium; I L high threshold; I T low threshold; I N; I_KD; I M; I Na,t;
Gap Junctions:
Receptor(s): GabaA; GabaB; AMPA; mGluR;
Gene(s): HCN1;
Transmitter(s): Gaba; Glutamate;
Simulation Environment: NEURON; Python;
Model Concept(s): Oscillations; Activity Patterns; Beta oscillations; Reaction-diffusion; Calcium dynamics; Pathophysiology; Multiscale;
Implementer(s): Neymotin, Sam [samn at neurosim.downstate.edu]; Dura-Bernal, Salvador [salvadordura at gmail.com];
Search NeuronDB for information about:  Neocortex V1 L6 pyramidal corticothalamic cell; Neocortex V1 interneuron basket PV cell; Neocortex U1 L2/6 pyramidal intratelencephalic cell; GabaA; GabaB; AMPA; mGluR; I Na,t; I L high threshold; I N; I T low threshold; I A; I M; I h; I K,Ca; I Calcium; I_SERCA; I_KD; Ca pump; Gaba; Glutamate;
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dystdemo
readme.txt
cagk.mod
cal.mod *
calts.mod *
can.mod *
cat.mod *
gabab.mod
h_winograd.mod
HCN1.mod
IC.mod *
icalts.mod *
ihlts.mod *
kap.mod
kcalts.mod *
kdmc.mod
kdr.mod
km.mod *
mglur.mod *
misc.mod *
MyExp2SynBB.mod *
MyExp2SynNMDABB.mod
nax.mod
stats.mod *
vecst.mod *
aux_fun.inc *
conf.py
declist.hoc *
decnqs.hoc *
decvec.hoc *
default.hoc *
drline.hoc *
geom.py
ghk.inc *
grvec.hoc
init.hoc
labels.hoc
labels.py *
local.hoc *
misc.h
mpisim.py
netcfg.cfg
nqs.hoc *
nqs.py
nrnoc.hoc *
pyinit.py *
python.hoc *
pywrap.hoc *
simctrl.hoc *
simdat.py
syn.py
syncode.hoc *
vector.py *
xgetargs.hoc *
                            
TITLE L-calcium channel
: L-type calcium channel with [Ca]i inactivation
: from Jaffe, D. B., Ross, W. N., Lisman, J. E., Laser-Ross, N., Miyakawa, H., and Johnston, D. A. A model for dendritic Ca2
: accumulation in hippocampal pyramidal neurons based on fluorescence imaging measurements. J. Neurophysiol. 71:1O65-1077 1994.
: conduction density estimate of 50-200 pS/mu2; 0.0025 S/cm2 (5-20 channels of 10 each)
: M. Migliore, E. Cook, D.B. Jaffe, D.A. Turner and D. Johnston, Computer simulations of morphologically reconstructed CA3
: hippocampal neurons, J. Neurophysiol. 73, 1157-1168 (1995). 
: adapted from http://senselab.med.yale.edu/modeldb/ShowModel.asp?model=3263&file=\ca3_db\cal2.mod
: this version from https://senselab.med.yale.edu/ModelDB/ShowModel.asp?model=148094&file=\kv72-R213QW-mutations\cal2.mod
: Miceli F, Soldovieri MV, Ambrosino P, Barrese V, Migliore M, Cilio MR, Taglialatela M (2013) Genotype-phenotype
: correlations in neonatal epilepsies caused by mutations in the voltage sensor of Kv7.2 potassium channel subunits. PNAS 110:4386-4391

UNITS {
  (mA) = (milliamp)
  (mV) = (millivolt)

  FARADAY = 96520 (coul)
  R = 8.3134 (joule/degC)
  KTOMV = .0853 (mV/degC)
}

PARAMETER {
  v (mV)
  celsius 	(degC)
  gcalbar=.003 (mho/cm2)
  ki=.001 (mM)
  cai = 50.e-6 (mM)
  cao = 2 (mM)
  q10 = 5
  mmin=0.2
  tfa = 1
  a0m =0.1
  zetam = 2
  vhalfm = 4
  gmm=0.1	
  ggk
}


NEURON {
  SUFFIX cal
  USEION ca READ cai,cao WRITE ica
  RANGE gcalbar,cai, ica, gcal, ggk
  RANGE minf,tau
}

STATE {
  m
}

ASSIGNED {
  ica (mA/cm2)
  gcal (mho/cm2)
  minf
  tau   (ms)
}

INITIAL {
  rate(v)
  m = minf
  gcal = gcalbar*m*m*h2(cai)
  ggk=ghk(v,cai,cao)
  ica = gcal*ggk
}

BREAKPOINT {
  SOLVE state METHOD cnexp
  gcal = gcalbar*m*m*h2(cai)
  ggk=ghk(v,cai,cao)
  ica = gcal*ggk
}

FUNCTION h2(cai(mM)) {
  h2 = ki/(ki+cai)
}


FUNCTION ghk(v(mV), ci(mM), co(mM)) (mV) {
  LOCAL nu,f
  f = KTF(celsius)/2
  nu = v/f
  ghk=-f*(1. - (ci/co)*exp(nu))*efun(nu)
}

FUNCTION KTF(celsius (DegC)) (mV) {
  KTF = ((25./293.15)*(celsius + 273.15))
}


FUNCTION efun(z) {
  if (fabs(z) < 1e-4) {
    efun = 1 - z/2
  }else{
    efun = z/(exp(z) - 1)
  }
}

FUNCTION alp(v(mV)) (1/ms) {
  alp = 15.69*(-1.0*v+81.5)/(exp((-1.0*v+81.5)/10.0)-1.0)
}

FUNCTION bet(v(mV)) (1/ms) {
  bet = 0.29*exp(-v/10.86)
}

FUNCTION alpmt(v(mV)) {
  alpmt = exp(0.0378*zetam*(v-vhalfm)) 
}

FUNCTION betmt(v(mV)) {
  betmt = exp(0.0378*zetam*gmm*(v-vhalfm)) 
}

DERIVATIVE state {  
  rate(v)
  m' = (minf - m)/tau
}

PROCEDURE rate(v (mV)) { :callable from hoc
  LOCAL a, b, qt
  qt=q10^((celsius-25)/10)
  a = alp(v)
  b = 1/((a + bet(v)))
  minf = a*b
  tau = betmt(v)/(qt*a0m*(1+alpmt(v)))
  if (tau<mmin/qt) {tau=mmin/qt}
}

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