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

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" ... 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. ..."
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 L5/6 pyramidal GLU cell; Neocortex U1 L2/6 pyramidal intratelencephalic GLU cell; Neocortex V1 interneuron basket PV GABA 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 [Samuel.Neymotin at]; Dura-Bernal, Salvador [salvadordura at];
Search NeuronDB for information about:  Neocortex L5/6 pyramidal GLU cell; Neocortex V1 interneuron basket PV GABA cell; Neocortex U1 L2/6 pyramidal intratelencephalic GLU 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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: $Id: Ih.mod,v 1.1 2012/10/04 19:33:55 samn Exp $ 
TITLE Hyperpolarization-activated current Ih
  Model of the Hyperpolarization-activated current Ih, also called
  the "Anomalous Rectifier".  Cationic (Na/K) channel based on 
  data from thalamic relay neurons.

  Voltage dependence: derived from the data and models given in
  Huguenard & McCormick, J Neurophysiol. 68: 1373-1383, 1992, based
  on voltage-clamp characterization of the Ih current in thalamic
  neurons by McCormick & Pape, J. Physiol. 431: 291, 1990.

  Calcium regulation: the model includes one of the features of Ih in
  thalamic neurons (and elsewhere), which is the regulation of this
  current by intracellular calcium.  Voltage-clamp experiments of 
  Ih in heart cells (Harigawa & Irisawa, J. Physiol. 409: 121, 1989)
  showed that intracellular calcium induces a shift in the voltage-
  dependent activation of the current.  This shift can be reproduced
  by assuming that calcium binds only to the open state of the 
  channel, "locking" Ih in the open configuration (see Destexhe et 
  al., Biophys J. 65: 1538-1552, 1993).  It was later found that 
  calcium does not bind directly to Ih, but cAMP binds to the open
  state of the channel, and cAMP production is stimulated by 
  calcium (Luthi and McCormick, Nat. Neurosci. 2: 634-641, 1999).
  The present model simulates such "indirect" regulation by calcium
  and is a modified version from the model given in Destexhe et al.,
  J. Neurophysiol. 76: 2049-2070, 1996.

  See also


	  Normal voltage-dependent opening of Ih channels:

		c1 (closed) <-> o1 (open)	; rate cst alpha(V),beta(V)

	  Ca++ binding on second messenger

		p0 (inactive) + nca Ca <-> p1 (active)	; rate cst k1,k2

	  Binding of active messenger on the open form (nexp binding sites) :

		o1 (open) + nexp p1 <-> o2 (open)	; rate cst k3,k4

	It is more useful to reformulate the parameters k1,k2 into
	k2 and cac = (k2/k1)^(1/nca) = half activation calcium dependence, 
	and idem for k3,k4 into k4 and Pc = (k4/k3)^(1/nexp) = half activation
	of Ih binding (this is like dealing with tau_m and m_inf instead of
	alpha and beta in Hodgkin-Huxley equations)
	- k2:	this rate constant is the inverse of the real time constant of 
             	the binding of Ca to the 2nd messenger
	- cac:	the half activation (affinity) of the 2nd messenger;
		around 1 to 10 microM.  
	- k4:	this rate constant is the inverse of the real time constant of 
             	the binding of the 2nd messenger to Ih channels
		very low, of the order of seconds (Luthi and McCormick, 1999)
	- Pc:	the half activation (affinity) of the Ih channels for the
		2nd messenger;
	- nca:	number of binding sites of calcium on 2nd messenger; usually 4
	- nexp:	number of binding sites on Ih channels
        - ginc: augmentation of conductance associated with the Ca bound state
	        (about 2-3; see Harigawa & Hirisawa, 1989)

 Alain Destexhe,


  SUFFIX hcnwino
  USEION hwino READ ehwino WRITE ihwino VALENCE 1
  USEION ca READ cai
  RANGE ghbar, m, o1, o2, p0, p1, k2, alpha, beta
  GLOBAL cac, k4, Pc, nca, nexp, ginc, qt, origtemp

  (molar)	= (1/liter)
  (mM)	= (millimolar)
  (mA) 	= (milliamp)
  (mV) 	= (millivolt)
  (msM)	= (ms mM)

  ehwino = -20	(mV)
  celsius = 37	(degC)
  ghbar	= 2e-5 (mho/cm2)
  cac = 0.006 (mM)		: half-activation of calcium dependence
  k2 = 0.0001 (1/ms)		: inverse of time constant
  Pc = 0.01			: half-activation of CB protein dependence
  k4 = 0.001	(1/ms)		: backward binding on Ih
  nca = 4			: number of binding sites of ca++
  nexp= 1			: number of binding sites on Ih channels
  ginc= 2			: augmentation of conductance with Ca++
  q10 = 2.2
  origtemp = 26 : temperature at which experiments performed -- Harnett 2015 J Neurosci
  qt = 1.2668546920110242 : q10^((celsius-34)/10)

  c1	: closed state of channel
  o1	: open state
  o2	: CB-bound open state
  p0	: resting CB
  p1	: Ca++-bound CB

  v	(mV)
  cai	(mM)
  ihwino (mA/cm2)
  gh	(mho/cm2)
  alpha	(1/ms)
  beta	(1/ms)
  k1ca	(1/ms)
  k3p	(1/ms)

  SOLVE ihkin METHOD sparse
  m = o1 + ginc * o2
  ihwino = ghbar * m * (v - ehwino)

KINETIC ihkin {
:  Here k1ca and k3p are recalculated at each call to evaluate_fct
:  because Ca or p1 have to be taken at some power and this does
:  not work with the KINETIC block.
:  So the kinetics is actually equivalent to
:	c1 <-> o1
:	p0 + nca Cai <-> p1
:	o1 + nexp p1 <-> o2
  ~ c1 <-> o1		(alpha,beta)
  ~ p0 <-> p1		(k1ca,k2)
  ~ o1 <-> o2		(k3p,k4)
  CONSERVE p0 + p1 = 1
  CONSERVE c1 + o1 + o2 = 1

:  Experiments of McCormick & Pape were at 36 deg.C
:  Q10 is assumed equal to 3
  : tadj = 3.0 ^ ((celsius-36 (degC) )/10 (degC) )
  : rate(v)
  : h = h_inf
  qt = q10^((celsius-origtemp)/10)
  c1 = 1
  o1 = 0
  o2 = 0
  p0 = 1
  p1 = 0

PROCEDURE evaluate_fct(v (mV), cai (mM)) {
  alpha = qt / exp(9.63 + 0.0458 * v) 
  beta = qt / exp(1.30  - 0.0447 * v) 
  k1ca = k2 * (cai/cac)^nca
  k3p = k4 * (p1/Pc)^nexp

:  procedure for evaluating the activation curve of Ih
PROCEDURE activation(v (mV), cai (mM)) { LOCAL cc
  cc = 1 / (1 + (cac/cai)^nca ) 		: equil conc of CB-protein
  m = 1 / ( 1 + beta/alpha + (cc/Pc)^nexp )
  m = ( 1 + ginc * (cc/Pc)^nexp ) * m

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