Computer model of clonazepam`s effect in thalamic slice (Lytton 1997)

 Download zip file   Auto-launch 
Help downloading and running models
Accession:12631
Demonstration of the effect of a minor pharmacological synaptic change at the network level. Clonazepam, a benzodiazepine, enhances inhibition but is paradoxically useful for certain types of seizures. This simulation shows how inhibition of inhibitory cells (the RE cells) produces this counter-intuitive effect.
Reference:
1 . Lytton WW (1997) Computer model of clonazepam's effect in thalamic slice. Neuroreport 8:3339-43 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Realistic Network;
Brain Region(s)/Organism: Thalamus;
Cell Type(s): Thalamus geniculate nucleus (lateral) principal neuron; Thalamus reticular nucleus cell;
Channel(s): I Na,t; I T low threshold; I K; I CAN;
Gap Junctions:
Receptor(s): GabaA; Gaba;
Gene(s):
Transmitter(s): Gaba;
Simulation Environment: NEURON;
Model Concept(s): Activity Patterns; Bursting; Therapeutics; Epilepsy; Calcium dynamics;
Implementer(s): Lytton, William [billl at neurosim.downstate.edu];
Search NeuronDB for information about:  Thalamus geniculate nucleus (lateral) principal neuron; Thalamus reticular nucleus cell; GabaA; Gaba; I Na,t; I T low threshold; I K; I CAN; Gaba;
/
lytton97b
README
AMPA.mod
calciumpump_destexhe.mod *
GABAA.mod
GABAB1.mod
GABALOW.mod
HH_traub.mod *
IAHP_destexhe.mod
ICAN_destexhe.mod
ICAN_voltdep.mod
Ih_old.mod *
IT_wang.mod
IT2_huguenard.mod
NMDA.mod
passiv.mod *
pregen.mod *
presyn.mod *
pulse.mod
rand.mod
bg.inc *
boxes.hoc
ctl.dat
ctlnew.dat
czp.dat
czpnew.dat
declist.hoc *
decvec.hoc *
default.hoc *
disp.hoc
Fig3.gif
Fig4.gif
geom.hoc
grvec.hoc
init.hoc
labels.hoc
local.hoc
mod_func.c
mosinit.hoc
network.hoc
neurrep8
nrnoc.hoc
params.hoc
presyn.inc *
queue.inc *
run.hoc
show.hoc
simctrl.hoc *
sns.inc *
snsarr.inc
snscode.hoc
snsgr.hoc
snshead.inc *
synq.inc *
xtmp
                            
: $Id: Ih_old.mod,v 1.6 1995/02/16 22:18:58 ethomas Exp $
TITLE anomalous rectifier channel
COMMENT
:
: Anomalous Rectifier Ih - cation (Na/K) channel
: Differential equations
:
: Model of double activation (Destexhe & Babloyantz, 1992)
: Activation functions were fitted from 
: McCormick & Pape,  J. Physiol. 431: 291, 1990.
: and Soltesz et al, J. Physiol. 441: 175, 1991.
:
: Kinetic model of calcium-induced shift in the activation of Ih channels
: Model of A. Destexhe, 1992, inspired from the dependence of If on calcium
: in heart cells (Harigawa & Hirishawa, J. Physiol. 409: 121, 1989)
:
:   ACTIVATE BINDING MODEL : 
:       - binding of Ca on S and F channels (VERSION 2: nexp binding sites)
:       - Ca binds on activated gates (rate constants k1 and k2)
:	    idem before:
:		s0 (closed) <-> s1 (open)	; rate cst alpha1,beta1
:		f0 (closed) <-> f1 (open)	; rate cst alpha1,beta1

:	    new:
:		s1 (open) + Ca <-> s2 (open)	; rate cst k1,k2
:		f1 (open) + Ca <-> f2 (open)	; rate cst k1,k2
:
:       - this suffies to account for shift of Ih activation with calcium
:	  (no need of other mechanism - or other time constants than k1,k2)
:
:   PARAMETERS:
:
:     VERSION 2: reformulation of parameters k1,k2 into k2 and cac.
:	cac = (k2/k1)^(1/nexp) = half activation calcium dependence.
:	- k2:  this rate constant is the inverse of the real time constant of 
:              the binding of Ca to Ih channel.  (0.001 to 0.0001 ms-1)
:	- cac: the half activation must be adapted to calcium dynamics of
:	       the cell.  Usually, cac = 1e-4 mM.
:	- nexp:number of sites of calcium on h-channels, nexp=2 here.
:
:  MODIF: addition of control variables (June 11 93)
:
: Written by Alain Destexhe, Salk Institute, Aug 1992
:
ENDCOMMENT

INDEPENDENT {t FROM 0 TO 1 WITH 1 (ms)}

NEURON {
	SUFFIX iar
	USEION other WRITE iother VALENCE 1
	USEION ca READ cai
        RANGE ghbar, gh, i
	GLOBAL k2, cac, nexp, h_inf, tau_s, tau_f, controls, controlf
}

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


PARAMETER {
	eh	= -43	(mV)
	celsius = 36	(degC)
	ghbar	= .0001	(mho/cm2)
	cac	= 1e-4	(mM)		: half-activation of calcium dependence
	k2	= 0.001	(1/ms)		: inverse of time constant
	nexp	= 2			: number of binding sites
	controls = 1			: control of variable s (0=no s1, s2)
	controlf = 1			: control of variable f (0=no f1, f2)
}


STATE {
	s1
	s2
	f1
	f2
}


ASSIGNED {
	v	(mV)
	cai	(mM)
	i	(mA/cm2)
	iother	(mA/cm2)
        gh	(mho/cm2)
	h_inf
	tau_s	(ms)
	tau_f	(ms)
	alpha1	(1/ms)
	alpha2	(1/ms)
	beta1	(1/ms)
	beta2	(1/ms)
	kk	(1/ms)
	fderiv	(1/ms)
	tadj
}


BREAKPOINT {
	SOLVE states METHOD runge

	if(controls == 0) {
		gh = ghbar * (f1+f2)
	} else if(controlf == 0) {
		gh = ghbar * (s1+s2)
	} else {
		gh = ghbar * (s1+s2) * (f1+f2)
	}
	
	i = gh * (v - eh)
	iother = i
}

DERIVATIVE states { LOCAL s0,f0
	evaluate_fct(v)

	s0 = 1 - s1 - s2
	f0 = 1 - f1 - f2

	kk = k2 * (5e-5/cac)^nexp

	fderiv = kk*s1 - k2*s2

	s1' = alpha1*s0 - beta1*s1 - fderiv
	s2' = fderiv

	fderiv = kk*f1 - k2*f2

	f1' = alpha2*f0 - beta2*f1 - fderiv
	f2' = fderiv
}

UNITSOFF
INITIAL {
:
:  Experiments of Coulter et al were at 36 deg.C
:  Q10 is assumed equal to 3
:
        tadj = 3.0 ^ ((celsius-36)/10)
	evaluate_fct(v)
	kk = k2 * (cai/cac)^nexp
	s1 = alpha1*k2/(alpha1*kk + alpha1*k2 + beta1*k2)
	s2 = alpha1*kk/(alpha1*kk + alpha1*k2 + beta1*k2)
	f1 = alpha2*k2/(alpha2*kk + alpha2*k2 + beta2*k2)
	f2 = alpha2*kk/(alpha2*kk + alpha2*k2 + beta2*k2)
}


PROCEDURE evaluate_fct(v (mV)) {

	h_inf = 1 / ( 1 + exp((v+68.9)/6.5) )	: sigmoide "square root"
	tau_s = exp((v+183.6)/15.24) / tadj	: version J neuro
	tau_f = exp((v+158.6)/11.2) / ( 1 + exp((v+75)/5.5) ) / tadj

	alpha1 = controls * h_inf / tau_s
	beta1  = ( 1 - h_inf ) / tau_s
	alpha2 = controlf * h_inf / tau_f
	beta2  = ( 1 - h_inf ) / tau_f
}
UNITSON


Lytton WW (1997) Computer model of clonazepam's effect in thalamic slice. Neuroreport 8:3339-43[PubMed]

References and models cited by this paper

References and models that cite this paper

Andersen P, Andersson S (1968) Physiological Basis Of The Alpha Rhythm

Ashizawa N, Nakamura T, Watanabe T (1977) Studies on luciferase from Photobacterium phosphoreum. IX. Further studies on the spectroscopic characteristics of the enzyme-FMN intermediates. J Biochem (Tokyo) 81:1057-62 [PubMed]

Bal T, McCormick DA (1993) Mechanisms of oscillatory activity in guinea-pig nucleus reticularis thalami in vitro: a mammalian pacemaker. J Physiol 468:669-91 [PubMed]

Coulter DA, Huguenard JR, Prince DA (1989) Calcium currents in rat thalamocortical relay neurones: kinetic properties of the transient, low-threshold current. J Physiol 414:587-604 [PubMed]

Destexhe A, Mainen ZF, Sejnowski TJ (1994) Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism. J Comput Neurosci 1:195-230 [Journal] [PubMed]

   Application of a common kinetic formalism for synaptic models (Destexhe et al 1994) [Model]
   Kinetic synaptic models applicable to building networks (Destexhe et al 1998) [Model]

Destexhe A, Sejnowski TJ (1995) G protein activation kinetics and spillover of gamma-aminobutyric acid may account for differences between inhibitory responses in the hippocampus and thalamus. Proc Natl Acad Sci U S A 92:9515-9 [PubMed]

Dreifuss FE, Penry JK, Rose SW, Kupferberg HJ, Dyken P, Sato S (1975) Serum clonazepam concentrations in children with absence seizures. Neurology 25:255-8 [PubMed]

Gloor P, Fariello RG (1988) Generalized epilepsy: some of its cellular mechanisms differ from those of focal epilepsy. Trends Neurosci 11:63-8 [PubMed]

Golomb D, Wang XJ, Rinzel J (1996) Propagation of spindle waves in a thalamic slice model. J Neurophysiol 75:750-69 [Journal] [PubMed]

Gutnick MJ, Prince DA (1975) Effects of projected cortical epileptiform discharges on neuronal activities in ventrobasal thalamus of the cat: ictal discharge. Exp Neurol 46:418-31 [PubMed]

Hines M (1993) NEURON--a program for simulation of nerve equations. Neural Systems: Analysis And Modeling, Eeckman F, ed. pp.127

Huguenard JR, Prince DA (1992) A novel T-type current underlies prolonged Ca(2+)-dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus. J Neurosci 12:3804-17 [PubMed]

Huguenard JR, Prince DA (1994) Clonazepam suppresses GABAB-mediated inhibition in thalamic relay neurons through effects in nucleus reticularis. J Neurophysiol 71:2576-81 [Journal] [PubMed]

Lytton WW (1997) Brain organization: from molecules to parallel processing Contemporary Behavioral Neurology, Trimble M:Cummings J, ed. pp.5

Lytton WW, Contreras D, Destexhe A, Steriade M (1997) Dynamic interactions determine partial thalamic quiescence in a computer network model of spike-and-wave seizures. J Neurophysiol 77:1679-96 [Journal] [PubMed]

   Thalamic quiescence of spike and wave seizures (Lytton et al 1997) [Model]

Lytton WW, Destexhe A, Sejnowski TJ (1996) Control of slow oscillations in the thalamocortical neuron: a computer model. Neuroscience 70:673-84 [PubMed]

Mody I, De Koninck Y, Otis TS, Soltesz I (1994) Bridging the cleft at GABA synapses in the brain. Trends Neurosci 17:517-25 [PubMed]

Otis TS, Mody I (1992) Modulation of decay kinetics and frequency of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents in hippocampal neurons. Neuroscience 49:13-32 [PubMed]

Pinault D, Bourassa J, Deschaenes M (1995) The axonal arborization of single thalamic reticular neurons in the somatosensory thalamus of the rat. Eur J Neurosci 7:31-40 [PubMed]

Pinault D, Bourassa J, Deschaenes M (1995) Thalamic reticular input to the rat visual thalamus: a single fiber study using biocytin as an anterograde tracer. Brain Res 670:147-52 [PubMed]

Rogers CJ, Twyman RE, Macdonald RL (1994) Benzodiazepine and beta-carboline regulation of single GABAA receptor channels of mouse spinal neurones in culture. J Physiol 475:69-82 [PubMed]

Ulrich D, Huguenard JR (1996) GABAB receptor-mediated responses in GABAergic projection neurones of rat nucleus reticularis thalami in vitro. J Physiol 493 ( Pt 3):845-54 [PubMed]

Ulrich D, Huguenard JR (1997) Nucleus-specific chloride homeostasis in rat thalamus. J Neurosci 17:2348-54 [PubMed]

Vergnes M, Marescaux C, Micheletti G, Depaulis A, Rumbach L, Warter JM (1984) Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mal-like epilepsy. Neurosci Lett 44:91-4 [PubMed]

Destexhe A, Sejnowski TJ (2003) Interactions between membrane conductances underlying thalamocortical slow-wave oscillations. Physiol Rev 83:1401-53 [PubMed]

Hines ML, Carnevale NT (2003) Personal Communication of NEURON bibliography

(26 refs)