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

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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;
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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
                            
//  $Header: /u/billl/nrniv/tcre/RCS/local.hoc,v 1.3 2002/07/23 15:20:16 billl Exp $
//
//  This file contains local modifications to nrnoc.hoc and default.hoc
//
//  Users should not edit nrnoc.hoc or default.hoc.  Any local 
//  changes to these files should be made in this file.

// ------------------------------------------------------------
//* MODIFICATIONS TO NRNOC.HOC
// The procedures declared here will overwrite any duplicate
// procedures in nrnoc.hoc.
// ------------------------------------------------------------

print "WARNING: local local.hoc $Id: local.hoc,v 1.3 2002/07/23 15:20:16 billl Exp $"

//** proc initMech: initialization of mechanism variables
proc initMech() { // Initialization of mechanism variables 
     // NOTE: if any changes are made to the NEURON block of any local mod
     //       file, the user must add the necessary inits to initMisc1() 

   // Range variables 

    forall {
      if (ismembrane("na_ion")) { 
        nai = na_init
        nai0_na_ion = na_init
      }
      
      if (ismembrane("k_ion")) {
        ki = k_init
        ki0_k_ion = k_init
      }
      
      if (ismembrane("ca_ion")) { 
        cai = ca_init
        cai0_ca_ion = ca_init
      }

    }
}

strdef secnm
secnm = "XXXX"
func setother() {}
//** proc setMemb
proc setMemb() { local isum, aca, prevwarn
  prevwarn = 1e10 // flag for previous warning given

  forall {
    isum = 0.0
    if (ismembrane("Pass")) {
      if (ismembrane("na_ion"))   { isum = isum + ina   }
      if (ismembrane("k_ion"))    { isum = isum + ik    }
      if (ismembrane("ca_ion"))   { isum = isum + ica   }
      if (ismembrane("other_ion")){ isum = isum + iother}
      isum += setother()
      
      ifsec secnm print isum
      if (isum == 0) { /* passive cmp so set erev = vrest */
        erev_Pass = v
      } else {
        /* assume that g has been set and determine erev */
        if (g_Pass > 0) {
          erev_Pass = v + isum/g_Pass 
        } else {
          if (erev_Pass != v) { 
            g_Pass = isum/(erev_Pass - v) 
          }
        }
      }
      
      /* pick out the screw ups */
      if (g_Pass <= 0) {
        sectionname(section)
        printf("ERROR: bad g (%g) in segment %s.\n",g_Pass, section)  }
        if ((erev_Pass < -100 || erev_Pass > -50) && erev_Pass!=prevwarn) {
          sectionname(section)
          // printf("WARNING: erev (%g) out of bounds in segment %s.\n",erev_Pass, section) 
          prevwarn = erev_Pass }
    }
    /* Alain's M-M pump */
    if (ismembrane("cad")) {
      kd_cad = cai*(-(cai * depth_cad *FARADAY) + cainf_cad * depth_cad * FARADAY - \
                    5000*ica*taur_cad - depth_cad * FARADAY*kt_cad * taur_cad)
      kd_cad = kd_cad/(cai*depth_cad*FARADAY - cainf_cad * depth_cad * FARADAY + \
                       5000*ica*taur_cad)
    }
    /* handle ca using cadecay */
    if (ismembrane("cadecay")) {
      k0_cadecay = ica
    }
    if (ismembrane("cadxp")) { 
      /* steady state : aca=pumpca/pump */
      icaex_cadxp = 0.0 /* temporary to compare with old neuron */
      aca = (k4_cadxp*cao + k1_cadxp*cai)/(k2_cadxp + k3_cadxp)
      /* set pump density to allow it to compensate incoming currents */
      pump_cadxp = -(ica+icaex_cadxp)/((1e3)*2*FARADAY*(k3_cadxp*aca - k4_cadxp*cao))
      pumpca_cadxp = aca*pump_cadxp
      printf("CA pump init: %g %g %g %g %g\n",aca,pump_cadxp,pumpca_cadxp,ica,icaex_cadxp)
    }
  }
}

//------------------------------------------------------------
//*MODIFICATIONS TO DEFAULT.HOC
//
// Vars added here may not be handled properly within nrnoc.hoc
//------------------------------------------------------------

//** String defaults

//** Simulation defaults

long_dt     = .001      // msec 

objref sfunc,tmpfile
sfunc = new StringFunctions()   // needed to use is_name()
tmpfile = new File()  // check for existence before opening a user's local.hoc file

proc write_comment () {
  tmpfile.aopen("index")
  tmpfile.printf("%s\n",$s1)
  tmpfile.close()  
}

func asin () { return atan($1/sqrt(1-$1*$1)) }
func acos () { return atan(sqrt(1-$1*$1)/$1) }

condor_run = 0  // define for compatability

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]

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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]
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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]

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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]

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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

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