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]
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 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 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 *
                            
COMMENT
	calcium accumulation into a volume of area*depth next to the
	membrane with a decay (time constant tau) to resting level
	given by the global calcium variable cai0_ca_ion
	Modified to include a resting current (irest) and peak value
	(cmax)
	i is a dummy current needed to force a BREAKPOINT
	Note: irest cancels out resting calcium current contributions
	by mechanisms that write ica.  To initialize irest properly
	use a custom proc init that assigns values to irest as illustrated
	in this excerpt:
	finitialize(Vrest) // use v_init if want to change.
        fcurrent()
	forall if (ismembrane("cacum")) {
	       for(x,0) irest_cacum(x)=ica(x) // (fixed from =-ica minus sign bug)
	}

ENDCOMMENT

NEURON {
	SUFFIX cacum
	USEION ca READ ica WRITE cai
	NONSPECIFIC_CURRENT i
	RANGE depth, tau, cai0, cmax, irest, ca_tmax
}

UNITS {
        (um) = (micron)
	(mM) = (milli/liter)
	(mA) = (milliamp)
	F = (faraday) (coulombs)
}

PARAMETER {
	depth = 0.1 (um)	: assume volume = area*depth
	irest = 0  (mA/cm2)		: to be initialized in hoc	
	tau = 100 (ms) :  ~40 ms phenomenologically fits dendrite shafts, ~350 ms fits spines (murthy et al 2000 PNAS, earlier model default was 100 (ms)
	cai0 = 50e-6 (mM)	: Requires explicit use in INITIAL
			: block for it to take precedence over cai0_ca_ion
			: Do not forget to initialize in hoc if different
			: from this default.
}

ASSIGNED {
        ica      (mA/cm2)
        cmax     (milli/liter)
        ca_tmax  (ms)
        i        (mA/cm2)
}

STATE {
	cai (mM)
}

INITIAL {
	cai = cai0
:	irest = ica : this make simulations depend on end result of prior simulations
	cmax=cai
	ca_tmax=0
}

BREAKPOINT {
	SOLVE integrate METHOD derivimplicit
	if (cai>cmax) {cmax=cai ca_tmax=t}
	if (cai<0) {cai=0}
	i=0
}

DERIVATIVE integrate {
	cai' = -(ica+irest)/depth/F/2 * (1e4) + (cai0 - cai)/tau
}

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