CA1 pyramidal neuron: effects of R213Q and R312W Kv7.2 mutations (Miceli et al. 2013)

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Accession:148094
NEURON mod files from the paper: Miceli et al, Genotype–phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of Kv7.2 potassium channel subunits, PNAS 2013 Feb 25. [Epub ahead of print] In this paper, functional studies revealed that in homomeric or heteromeric configuration with KV7.2 and/or KV7.3 subunits, R213W and R213Q mutations markedly destabilized the open state, causing a dramatic decrease in channel voltage sensitivity. Modeling these channels in CA1 hippocampal pyramidal cells revealed that both mutations increased cell firing frequency, with the R213Q mutation prompting more dramatic functional changes compared with the R213W mutation.
Reference:
1 . Miceli F, Soldovieri MV, Ambrosino P, Barrese V, Migliore M, Cilio MR, Taglialatela M (2013) Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci U S A 110:4386-91 [PubMed]
Citations  Citation Browser
Model Information (Click on a link to find other models with that property)
Model Type: Channel/Receptor; 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 Calcium;
Gap Junctions:
Receptor(s):
Gene(s):
Transmitter(s):
Simulation Environment: NEURON;
Model Concept(s): Active Dendrites; Action Potentials; 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 Calcium;
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kv72-R213QW-mutations
readme.html
cacumm.mod
cad.mod
cagk.mod *
cal2.mod *
cat.mod *
h.mod *
kadist.mod *
KahpM95.mod *
kaprox.mod *
kdrca1.mod *
kv72wt73wt.mod *
kv72wt73wt72R213Q.mod
kv72wt73wt72R213W.mod
na3n.mod *
naxn.mod *
fig4a.hoc
fixnseg.hoc *
geo9068802.hoc *
mosinit.hoc *
                            
load_file("nrngui.hoc")
cvode_active(1)

dist=7
rel=0.5

numbasal=70

xopen("geo9068802.hoc")             // geometry file
xopen("fixnseg.hoc")           

Cm    = 0.75
Rm = 28000/Cm
RaAll= 500
RaAx = 50

Vrest = -65
dt = 0.1
gna =  .045
AXONM = 3
gkdr = 0.02
celsius = 35.0  
ka =  0.03
ghd=0.00001
gkm=0.014
gcat=0.0001
gahp=0.00001
perc=0

objref g, b,c, stim, s, rsyn, nc, m, gt, gk, count, apc, outfile

count=new Vector()
outfile=new File()

forsec "axon" {insert pas e_pas=Vrest g_pas = 1/Rm Ra=RaAx cm=Cm}
forsec "soma" {insert pas e_pas=Vrest g_pas = 1/Rm Ra=RaAll cm=Cm}
forsec "dendrite"{insert pas e_pas=Vrest g_pas = 1/Rm Ra=RaAll cm=Cm}
forsec "user5" {insert pas e_pas=Vrest g_pas = 1/Rm Ra=RaAll cm=Cm}

access soma

apc=new APCount(.5)
apc.record(count)

freq=50
geom_nseg()

axon {nseg=11}

distance()

stim = new IClamp(.5)
stim.del=5
stim.dur=500
stim.amp=0.65
inj=0.65

tstop=600

b = new VBox()
b.intercept(1)
g = new Graph()
g.size(0,tstop,-70,20)
g.xaxis(1)
g.exec_menu("10% Zoom out")
g.addexpr("v_soma","soma.v(rel)",1,1, 0.2,0.9,2)
xpanel("",1)
xpanel()
b.intercept(0)
b.map()



forsec "axon" {   
		insert kv72wt73wt
		insert kvR213Q
		insert kvR213W
                insert nax gbar_nax=gna*AXONM	
                insert kdr gkdrbar_kdr=gkdr*AXONM
                insert kap gkabar_kap = ka
}

forsec "soma" {  
		insert kv72wt73wt
		insert kvR213Q
		insert kvR213W
		insert hd ghdbar_hd=ghd	
                insert na3 gbar_na3=gna*AXONM
                insert kdr gkdrbar_kdr=gkdr*AXONM
                insert kap gkabar_kap = ka
                insert cat  gcatbar_cat=gcat
		insert cacum tau_cacum=100 depth_cacum=diam/2
		insert KahpM95 gbar_KahpM95 = gahp 
}

for i=0, numbasal-1 dendrite[i] {
                insert na3 gbar_na3=0
                insert cat  gcatbar_cat=gcat
		insert cacum tau_cacum=100 depth_cacum=diam/2
		insert KahpM95 gbar_KahpM95 = gahp 
}

                
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
		insert cacum tau_cacum=100 depth_cacum=diam/2
		insert KahpM95 gbar_KahpM95 = gahp 
                insert cat  gcatbar_cat=gcat

		for (x,0) { xdist = distance(x)
                	ghdbar_hd(x) = ghd*(1+3*xdist/100)
                		if (xdist > 100){
                        		gkabar_kad(x) = ka*(1+xdist/100)
                			} else {
                        		gkabar_kap(x) = ka*(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
		insert cacum tau_cacum=100 depth_cacum=diam/2
                insert cat  gcatbar_cat=gcat
		insert KahpM95 gbar_KahpM95 = gahp 

		for (x,0) { xdist = distance(x)
                	ghdbar_hd(x) = ghd*(1+3*xdist/100)
                		if (xdist > 100){
                        		gkabar_kad(x) = ka*(1+xdist/100)
                			} else {
                        		gkabar_kap(x) = ka*(1+xdist/100)
               				}
		}
}

proc init() {
	t=0

	stim.amp=inj

        forall {
        v=Vrest
        if (ismembrane("nax") || ismembrane("na3")) {ena=55}
        if (ismembrane("KahpM95") || 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("hd")) {e_pas(x)=e_pas(x)+i_hd(x)/g_pas(x)}
	if (ismembrane("cat")){e_pas(x)=e_pas(x)+ica(x)/g_pas(x)}
		}
	}
	cvode.re_init()
	cvode.event(tstop)
	access soma
	g.begin()
}

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

xpanel(" ")
xradiobutton("wt","setgw()",1)
xradiobutton("R213W","setgW()")
xradiobutton("R213Q","setgQ()")
xbutton("run", "run()")
xpanel()

proc setgw() {
	forsec "soma" {gbar_kv72wt73wt=gkm}
	forsec "axon" {gbar_kv72wt73wt=gkm*3}
	forsec "soma" {gbar_kvR213Q=0}
	forsec "axon" {gbar_kvR213Q=0}
	forsec "soma" {gbar_kvR213W=0}
	forsec "axon" {gbar_kvR213W=0}
}

proc setgQ() {
	forsec "soma" {gbar_kv72wt73wt=0}
	forsec "axon" {gbar_kv72wt73wt=0}
	forsec "soma" {gbar_kvR213Q=gkm}
	forsec "axon" {gbar_kvR213Q=gkm*3}
	forsec "soma" {gbar_kvR213W=0}
	forsec "axon" {gbar_kvR213W=0}
}

proc setgW() {
	forsec "soma" {gbar_kv72wt73wt=0}
	forsec "axon" {gbar_kv72wt73wt=0}
	forsec "soma" {gbar_kvR213Q=0}
	forsec "axon" {gbar_kvR213Q=0}
	forsec "soma" {gbar_kvR213W=gkm}
	forsec "axon" {gbar_kvR213W=gkm*3}
}
setgw()