Alcohol excites Cerebellar Golgi Cells by inhibiting the Na+/K+ ATPase (Botta et al.2010)

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Accession:127021
Patch-clamp in cerebellar slices and computer modeling show that ethanol excites Golgi cells by inhibiting the Na+/K+ ATPase. In particular, voltage-clamp recordings of Na+/K+ ATPase currents indicated that ethanol partially inhibits this pump and this effect could be mimicked by low concentrations of the Na+/K+ ATPase blocker ouabain. The partial inhibition of Na+/K+ ATPase in a computer model of the Golgi cell reproduced these experimental findings that established a novel mechanism of action of ethanol on neural excitability.
Reference:
1 . Botta P, de Souza FM, Sangrey T, De Schutter E, Valenzuela CF (2010) Alcohol excites cerebellar Golgi cells by inhibiting the Na+/K+ ATPase. Neuropsychopharmacology 35:1984-96 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell; Electrogenic pump;
Brain Region(s)/Organism: Cerebellum;
Cell Type(s): Cerebellum golgi cell;
Channel(s): Na/K pump;
Gap Junctions:
Receptor(s):
Gene(s): HCN1;
Transmitter(s):
Simulation Environment: NEURON;
Model Concept(s): Detailed Neuronal Models; Markov-type model; Alcohol Use Disorder;
Implementer(s): Simoes-de-Souza, Fabio [fabio.souza at ufabc.edu.br];
Search NeuronDB for information about:  Na/K pump;
/
Golgi_cell_NaKATPAse
sessions
README.html
Golgi_BK.mod *
Golgi_Ca_HVA.mod *
Golgi_Ca_LVA.mod *
Golgi_CALC.mod *
Golgi_CALC_ca2.mod *
Golgi_hcn1.mod *
Golgi_hcn2.mod *
Golgi_KA.mod *
Golgi_KM.mod *
Golgi_KV.mod *
Golgi_lkg.mod *
Golgi_Na.mod *
Golgi_NaP.mod *
Golgi_NaR.mod *
Golgi_SK2.mod *
K_conc.mod *
Na_conc.mod *
Pregen.mod *
pump.mod
Synapse.mod *
Channel_dynamics.hoc *
Golgi_ComPanel.hoc *
Golgi_count.txt
Golgi_Pump_Ouabain.ses
Golgi_template.hoc
mosinit.hoc
nerst
Save_data.hoc *
Screenshot20100716_4.02.55PM.png
Start_Golgi_Ouabain.hoc
Synapses.hoc *
utils.hoc *
                            
/*******Cerebellar Golgi Cell Model with Na+/K+ ATPase**********

Developers:    Fabio M Simoes de Souza & E De Schutter

Work Progress: July 2009 - Dec 2009

Developed At:  Okinawa Institute of Science and Technology
               Computational Neuroscience Unit
               Okinawa - Japan
	       
Model Published in: 
             Botta P, Simoes de Souza F, Sangrey T, De Schutter E, Valenzuela F (2010)
             Alcohol excites cerebellar Golgi cells by inhibiting the Na+/K+ ATPase.
             Neuropsychopharmacology 35: 1984-1996.

This script is a modification from a previous published GoC model (Solinas et al., 2007).
A Na+/K+ ATPase and ionic concentration pools for Na+, K+, Ca2+ were incorporated into the soma of the model. 
The equations that simulated the Na+/K+ ATPase are described in Table S10 of Takeuchi et al. (2006)

References:
Sergio M. Solinas, Lia Forti, Elisabetta Cesana, Jonathan Mapelli, Erik De Schutter and Egidio D`Angelo (2008) Computational reconstruction of pacemaking and intrinsic electroresponsiveness in cerebellar golgi cells. Frontiers in Cellular Neuroscience 1:1-12.

Takeuchi A, Tatsumi S, Sarai N, Terashima K, Matsuoka S, Noma A (2006) Ionic mechanisms of cardiac cell swelling induced by blocking Na+/K+ pump as revealed by experiments and simulation. J. G. Physiol. 128: 495-507.

********************************************/

xopen("$(NEURONHOME)/lib/hoc/noload.hoc") 
nrnmainmenu()
load_file("nrngui.hoc")
//nrncontrolmenu()

// Load the Golgi cell template
xopen("Golgi_template.hoc")
objref Golgi[1]
Golgi[0] = new Goc()

v_init = -60
dt = 0.025


access Golgi[0].soma

cvode.active(0)

// Set output
load_file("Save_data.hoc")
// Initialize the counter
simcnt = cplus()

// Plot the Vm of the major compartments
//load_file("sessions/Vm.ses")

// Initialize all mechanisms
tstop=1
run()
init()

// Create new data directory
strdef dirname, command
//sprint(dirname,"SimData_%d",simcnt)
sprint(dirname,"SimData",simcnt)
sprint(command,"mkdir -p %s",dirname)
system(command)
// Store the Scripts in the data directory
sprint(command,"mkdir -p %s/Scripts",dirname)
system(command)
sprint(command,"cp -r *.hoc *.mod sessions %s/Scripts/",dirname)
system(command)

// Synaptic activation
//xopen("Synapses.hoc")

// Model surface
cell_surf_um = 0
access Golgi[0].soma
soma_surf = area(0.5)*1e-8 // cm2
cell_surf_cm = cell_surf_cm + area(0.5)*1e-8*nseg
for i = 0,2 {
access Golgi[0].dend[i]
cell_surf_cm = cell_surf_cm + area(0.5)*1e-8*nseg}
dend_surf = cell_surf_cm - soma_surf
access Golgi[0].axon
axon_surf = area(0.5)*1e-8
cell_surf_cm = cell_surf_cm + area(0.5)*1e-8*nseg
conv_mA_pA = 1e9

// Load the Golgi control panel
//xopen("Golgi_ComPanel.hoc")

// Load scripts for electroresponsiveness study
load_file("utils.hoc")
access Golgi[0].soma
objref time_tr
time_tr = new Vector()
time_tr.record(&t)
print "Cell membrane area in um2 = ",cell_surf_cm*1e8

// Inject current with gaussian noise
access Golgi[0].soma
objref gnoise
gnoisestate = 0
gnoise = new IClamp(0.5)
gnoise.del = 1e9
gnoise.dur = 100000
gnoise.amp = 0
objref r
gauss_noise_amp = 0.032 // pA
r = new Random()
r.normal(0,gauss_noise_amp)
r.play(&gnoise.amp)

// Here we must choose where to place the VC and CC
// electrodes: soma or micropipette?
// use soma for gaussian noise injections!!!
// use the micropipette for all other simulations
// in order to reproduce the experimental setup
access Golgi[0].elec
// access Golgi[0].soma

// Current & Voltage Clamp elements
objref vclampy,cclampy[3]
vclampy = new VClamp(0.5)
cclampy[0] = new IClamp(0.5)
cclampy[1] = new IClamp(0.5)
objref store
store = new Vector()

tstop = 500


//create an electrode in the soma
objectvar stim

 stim= new IClamp(0.5)
 stim.del=0
 stim.dur=100
 stim.amp=0.0

//Opening Section
xopen("Golgi_Pump_Ouabain.ses")


celsius=23.0
print "celcius(degC): ", celsius

inakmax_nakpump=5
print "inakmax_nakpump: ", inakmax_nakpump


//ouabain=0.0 uM
ouabain_nakpump=0
print "Ouabain(mM): ", ouabain_nakpump

v_init = -60
//v_leak=-56.5
v_leak=-44.5

Golgi[0].soma.el_Golgi_lkg=v_leak
Golgi[0].dend[0].el_Golgi_lkg=v_leak
Golgi[0].dend[1].el_Golgi_lkg=v_leak
Golgi[0].dend[2].el_Golgi_lkg=v_leak
Golgi[0].axon.el_Golgi_lkg=v_leak
print "el_Golgi_lkg: ", Golgi[0].soma.el_Golgi_lkg


Golgi[0].soma.ko(0.5)=5
Golgi[0].soma.ki(0.5)=140
Golgi[0].soma.nao(0.5)=145
Golgi[0].soma.nai(0.5)=5

//TTX 
// Golgi[0].soma.gnabar_Golgi_Na(0.5)=0
// Golgi[0].soma.gnabar_Golgi_NaR(0.5)=0
// Golgi[0].soma.gbar_Golgi_NaP=0

xpanel("Alcohol increases Golgi cell firing")
  xbutton("Figure 7g from Botta et al. 2010","recreate()")
xpanel()

Graph[0].family(1) // allows color switching control
proc recreate() {
  Graph[0].color(1) // black
  ouabain_nakpump=0.0000
  print "ouabain(mM): ", ouabain_nakpump

  init()
  run()
  continuerun(500)

 Graph[0].color(9) // gray

//ouabain=0.1 uM	
  ouabain_nakpump=0.0001
  print "ouabain(mM): ", ouabain_nakpump
  init()
  run()
  continuerun(500)
}

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