Early-onset epileptic encephalopathy (Miceli et al. 2015)

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Accession:170030
Model files from the paper "Early-Onset Epileptic Encephalopathy Caused by Gain-of-Function Mutations in the Voltage Sensor of Kv7.2 and Kv7.3 Potassium Channel Subunits" by Francesco Miceli, Maria Virginia Soldovieri, Paolo Ambrosino, Michela De Maria, Michele Migliore, Rosanna Migliore, and Maurizio Taglialatela J Neurosci. 2015 Mar 4;35(9):3782-93. The file fig7C.hoc reproduces the simulations shown in Fig.7C of the paper.
Reference:
1 . Miceli F, Soldovieri MV, Ambrosino P, De Maria M, Migliore M, Migliore R, Taglialatela M (2015) Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J Neurosci 35:3782-93 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Dendrite;
Brain Region(s)/Organism: Hippocampus;
Cell Type(s): Hippocampus CA1 pyramidal GLU cell;
Channel(s): I Na,t; I A; I K; I M; I h;
Gap Junctions:
Receptor(s):
Gene(s):
Transmitter(s): Glutamate;
Simulation Environment: NEURON;
Model Concept(s): Epilepsy;
Implementer(s): Migliore, Michele [Michele.Migliore at Yale.edu];
Search NeuronDB for information about:  Hippocampus CA1 pyramidal GLU cell; I Na,t; I A; I K; I M; I h; Glutamate;
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Kv72_ModelDB
readme.html
h.mod *
kadist.mod *
kamt.mod *
kaprox.mod *
kdrca1.mod *
ks.mod *
kv72wt73wt.mod *
kv72wt73wtR201C.mod
na3n.mod *
naxn.mod *
netstims.mod *
fig7C.hoc
fixnseg.hoc *
geo5038804-S.hoc
mosinit.hoc
olm-t.hoc
screenshot1.png
screenshot2.png
                            
load_file("nrngui.hoc")
load_file("olm-t.hoc")
cvode_active(1)

numaxon=1
numsoma=2
numbasal=52
numapical=70
numtrunk=49

xopen("geo5038804-S.hoc")             // geometry file
xopen("fixnseg.hoc")           

Rm = 28000
RmDend = Rm
RmSoma = Rm
RmAx = Rm

Cm    = 1
CmSoma= Cm
CmAx  = Cm
CmDend = Cm

RaAll= 150
RaSoma=150  
RaAx = 50

Vrest = -65
dt = 0.1
gna =  .025
fact=0.053431452
gkm=0.0015
gkmINT=0.0015
AXONM = 5
gkdr = 0.01
celsius = 35.0  
KMULT =  0.03
KMULTP = 0.03
ghd=0.00005
factor=1
norm=1
mod=0

objref  syni, syn1, syn0, nsi, ns1, ns0, nci, nc1, nc0, inter, apc, b, g, c

inter = new OLM()  

forsec "axon" {insert pas e_pas=Vrest g_pas = 1/RmAx Ra=RaAx cm=CmAx}
forsec "soma" {insert pas e_pas=Vrest g_pas = 1/RmSoma Ra=RaSoma cm=CmSoma}
forsec "dendrite"{insert pas e_pas=Vrest g_pas = 1/RmDend Ra=RaAll cm=CmDend}
forsec "user5" {insert pas e_pas=Vrest g_pas = 1/RmDend Ra=RaAll cm=CmDend}

access soma

freq=50
geom_nseg()
tot=0
forall {tot=tot+nseg}
distance()

soma apc   = new APCount(0.5)   
apc.thresh = -20.  

tstop=1100


b = new VBox()
b.intercept(1)
g = new Graph()
g.size(0,tstop,-80,40)
g.addvar("inter.inta[0].v(0.5)",3,1,2*tstop,0,2)
g.label(0.3,0.1,"int (Kv7.2+Kv7.3)")
g.exec_menu("10% Zoom out")
g.xaxis(1)
c = new Graph()
c.size(0,tstop,-80,40)
c.xaxis(1)
c.addvar("soma[0].v(0.5)",2,1,2*tstop,0,2)
c.exec_menu("10% Zoom out")
c.label(0.3,0.1,"CA1 (Kv7.2+Kv7.3)")	
b.intercept(0)
b.map()

user5[6]{
//  excitatory synapse
syn1= new Exp2Syn(.5)
syn1.tau1=0.5
syn1.tau2=5
syn1.e=0

ns1 = new NetStim(.5)
ns1.start=100
ns1.number=50
ns1.interval=20
ns1.noise=0.5
ns1.seed(225345)
}
nc1 = new NetCon(ns1, syn1, 0, 0, 0.039)


inter.inta[0]{
//excitatory synapse on BC
		syni= new Exp2Syn(.5) 
		syni.tau1=0.5
		syni.tau2=5
		syni.e=0
	}

nci = new NetCon(ns1, syni, 0, 3, 0.022)

soma[0]{
// inhibitory synapse 
syn0= new Exp2Syn(.5) 
syn0.tau1=0.5
syn0.tau2=7
syn0.e=-80 
}


inter.inta[0] nc0 = new NetCon(&v(.5), syn0, 0, 3, 0.15)

forsec "inta" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkmINT*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkmINT*mod
}

forsec "axon" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkm*3*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkm*3*mod
				insert nax gbar_nax=gna * AXONM
                insert kdr gkdrbar_kdr=gkdr
                insert kap gkabar_kap = KMULTP
}

forsec "soma" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkm*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkm*mod
		insert hd ghdbar_hd=ghd	vhalfl_hd=-73
                insert na3 gbar_na3=gna
                insert kdr gkdrbar_kdr=gkdr
                insert kap gkabar_kap = KMULTP
}

for i=0, numbasal-1 dendrite[i] {
		insert hd ghdbar_hd=ghd vhalfl_hd=-73
                insert na3 gbar_na3=gna
                insert kdr gkdrbar_kdr=gkdr
		insert kap gkabar_kap=0
		insert kad gkabar_kad=0

		for (x) if (x>0 && x<1) { xdist = distance(x)
                	ghdbar_hd(x) = ghd*(1+3*xdist/100)
                		if (xdist > 100){
					vhalfl_hd=-81
                        		gkabar_kad(x) = KMULT*(1+xdist/100)
                			} else {
					vhalfl_hd=-73
                        		gkabar_kap(x) = KMULTP*(1+xdist/100)
               				}
		}
}
                
forsec "apical_dendrite" {
			insert hd ghdbar_hd=ghd
                insert na3 gbar_na3=gna
                insert kdr gkdrbar_kdr=gkdr
		insert kap gkabar_kap=0
		insert kad gkabar_kad=0

		for (x) if (x>0 && x<1) { xdist = distance(x)
                	ghdbar_hd(x) = ghd*(1+3*xdist/100)
                		if (xdist > 100){
					vhalfl_hd=-81
                        		gkabar_kad(x) = KMULT*(1+xdist/100)
                			} else {
					vhalfl_hd=-73
                        		gkabar_kap(x) = KMULTP*(1+xdist/100)
							}
		}
}

forsec "user5" {
			insert hd ghdbar_hd=ghd
                insert na3 gbar_na3=gna
                insert kdr gkdrbar_kdr=gkdr
		insert kap gkabar_kap=0
		insert kad gkabar_kad=0

		for (x) if (x>0 && x<1) { xdist = distance(x)
                	ghdbar_hd(x) = ghd*(1+3*xdist/100)
                		if (xdist > 100){
					vhalfl_hd=-81
                        		gkabar_kad(x) = KMULT*(1+xdist/100)
								} else {
					vhalfl_hd=-73
                        		gkabar_kap(x) = KMULTP*(1+xdist/100)
               				}
		}
}

proc init() {
	t=0
        forall { 
        v=Vrest
        if (ismembrane("nax") || ismembrane("na3")) {ena=55}
        if (ismembrane("kdr") || ismembrane("kap") || ismembrane("kad")) {ek=-90}
       if (ismembrane("hd") ) {ehd_hd=-30}
	}
	finitialize(Vrest)
        fcurrent()

        forall { 
	for (x) {
	if (ismembrane("na3") || ismembrane("nax")){e_pas(x)=v(x)+(ina(x)+ik(x))/g_pas(x)}
	if (ismembrane("kv72wt73wt")|| ismembrane("kv72wt73wtR201C")){e_pas(x)=v(x)-norm*ik_kv72wt73wt(x)/g_pas(x)-mod*ik_kv72wt73wtR201C(x)/g_pas(x)}
//	if (ismembrane("kv72wt73wtR201C")){e_pas(x)=*v(x)-mod*ik_kv72wt73wtR201C(x)/g_pas(x)}
	if (ismembrane("hd")) {e_pas(x)=e_pas(x)+i_hd(x)/g_pas(x)}//
		}
	}
	cvode.re_init()
	cvode.event(tstop)
	access soma
	g.begin()
	c.begin()
}


proc advance() {
	fadvance()
	g.plot(t)
	g.flush() 
	c.plot(t)
	c.flush() 
	doNotify()	
	}

xpanel(" ")
xlabel("  ")
xradiobutton("Kv7.2+Kv7.3","setKv72()",1)
xradiobutton("Kv7.2+Kv7.2R201C+Kv7.3","setKvR201C()")
xlabel("  ")
xbutton("run", "run()")
xpanel()


proc setKv72() {
norm=1
mod=0
forsec "inta" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkmINT*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkmINT*mod}
forsec "axon" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkm*3*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkm*3*mod}
forsec "soma" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkm*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkm*mod}
g.erase_all()	
c.erase_all()
g.size(0,tstop,-80,40)
g.addvar("inter.inta[0].v(0.5)",3,1,2*tstop,0,2)
g.label(0.3,0.1,"int (Kv7.2+Kv7.3)")
g.exec_menu("10% Zoom out")
g.xaxis(1)
c.size(0,tstop,-80,40)
c.xaxis(1)
c.addvar("soma[0].v(0.5)",2,1,2*tstop,0,2)
c.exec_menu("10% Zoom out")
c.label(0.3,0.1,"CA1 (Kv7.2+Kv7.3)")
ns1.seed(225345)
run()	
}

proc setKvR201C() {
norm=0
mod=1
forsec "inta" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkmINT*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkmINT*mod}
forsec "axon" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkm*3*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkm*3*mod}
forsec "soma" {   
		insert kv72wt73wt gbar_kv72wt73wt=gkm*norm
		insert kv72wt73wtR201C gbar_kv72wt73wtR201C=gkm*mod}
g.erase_all()	
c.erase_all()
g.size(0,tstop,-80,40)
g.addvar("inter.inta[0].v(0.5)",4,1,2*tstop,0,2)
g.exec_menu("10% Zoom out")
g.xaxis(1)
c.size(0,tstop,-80,40)
c.xaxis(1)
c.addvar("soma[0].v(0.5)",1,1,2*tstop,0,2)
c.exec_menu("10% Zoom out")
g.label(0.3,0.1,"int (Kv7.2+Kv7.2R201C+Kv7.3)")
c.label(0.3,0.1,"CA1 (Kv7.2+Kv7.2R201C+Kv7.3)")	
ns1.seed(225345)
run()
}

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