The APP in C-terminal domain alters CA1 neuron firing (Pousinha et al 2019)

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Accession:256388
"The amyloid precursor protein (APP) is central to AD pathogenesis and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothezise that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes. Using cellular, electrophysiological and behavioural techniques, we showed that pathological AICD levels weakens CA1 neuron firing activity through a gene transcription-dependent mechanism. Furthermore, increased AICD production in hippocampal neurons modifies oscillatory activity, specifically in the gamma frequency range, and disrupts spatial memory task. Collectively, our data suggest that AICD pathological levels, observed in AD mouse models and in human patients, might contribute to progressive neuron homeostatic failure, driving the shift from normal ageing to AD."
Reference:
1 . Pousinha PA, Mouska X, Bianchi D, Temido-Ferreira M, Rajão-Saraiva J, Gomes R, Fernandez SP, Salgueiro-Pereira AR, Gandin C, Raymond EF, Barik J, Goutagny R, Bethus I, Lopes LV, Migliore M, Marie H (2019) The Amyloid Precursor Protein C-Terminal Domain Alters CA1 Neuron Firing, Modifying Hippocampus Oscillations and Impairing Spatial Memory Encoding. Cell Rep 29:317-331.e5 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell;
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; I L high threshold; I_AHP;
Gap Junctions:
Receptor(s): NMDA;
Gene(s):
Transmitter(s): Glutamate;
Simulation Environment: NEURON;
Model Concept(s): Aging/Alzheimer`s; Oscillations; Action Potentials; Memory;
Implementer(s): Bianchi, Daniela [danielabianchi12 -at- gmail.com];
Search NeuronDB for information about:  Hippocampus CA1 pyramidal GLU cell; NMDA; I Na,t; I L high threshold; I A; I K; I M; I h; I_AHP; Glutamate;
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PousinhaMouskaBianchiEtAl2019
readme.txt
ANsyn.mod *
bgka.mod *
burststim2.mod *
cad.mod *
cagk.mod
cal.mod *
calH.mod *
car.mod *
cat.mod *
ccanl.mod *
d3.mod *
gskch.mod *
h.mod *
IA.mod
ichan2.mod *
Ih.mod *
kadist.mod *
kaprox.mod *
Kaxon.mod *
kca.mod *
Kdend.mod *
kdr.mod *
kdrax.mod *
km.mod *
Ksoma.mod *
LcaMig.mod *
my_exp2syn.mod *
na3.mod *
na3dend.mod *
na3notrunk.mod *
Naaxon.mod *
Nadend.mod *
nap.mod *
Nasoma.mod *
nax.mod *
nca.mod *
nmdanet.mod *
regn_stim.mod *
somacar.mod *
STDPE2Syn2.mod *
mosinit.hoc
pyramidal_cell4b.hoc
ranstream.hoc *
ses.ses
stim_cell.hoc *
testcell.hoc
                            
COMMENT
IA channel

Reference:

1.	Zhang, L. and McBain, J. Voltage-gated potassium currents in
	stratum oriens-alveus inhibitory neurons of the rat CA1
	hippocampus, J. Physiol. 488.3:647-660, 1995.

		Activation V1/2 = -14 mV
		slope = 16.6
		activation t = 5 ms
		Inactivation V1/2 = -71 mV
		slope = 7.3
		inactivation t = 15 ms
		recovery from inactivation = 142 ms

2.	Martina, M. et al. Functional and Molecular Differences between
	Voltage-gated K+ channels of fast-spiking interneurons and pyramidal
	neurons of rat hippocampus, J. Neurosci. 18(20):8111-8125, 1998.	
	(only the gkAbar is from this paper)

		gkabar = 0.0175 mho/cm2
		Activation V1/2 = -6.2 +/- 3.3 mV
		slope = 23.0 +/- 0.7 mV
		Inactivation V1/2 = -75.5 +/- 2.5 mV
		slope = 8.5 +/- 0.8 mV
		recovery from inactivation t = 165 +/- 49 ms  

3.	Warman, E.N. et al.  Reconstruction of Hippocampal CA1 pyramidal
	cell electrophysiology by computer simulation, J. Neurophysiol.
	71(6):2033-2045, 1994.

		gkabar = 0.01 mho/cm2
		(number taken from the work by Numann et al. in guinea pig
		CA1 neurons)

ENDCOMMENT

UNITS {
        (mA) = (milliamp)
        (mV) = (millivolt)
}
 
NEURON {
        SUFFIX IA
        USEION k READ ek WRITE ik
        RANGE gkAbar,ik
        GLOBAL ainf, binf, aexp, bexp, tau_b
}
 
INDEPENDENT {t FROM 0 TO 1 WITH 1 (ms)}
 
PARAMETER {
        v (mV)
        p = 5 (degC)
        dt (ms)
        gkAbar = 0.0165 (mho/cm2)	:from Martina et al.
        ek = -90 (mV)
	tau_a = 5 (ms)
}
 
STATE {
        a b
}
 
ASSIGNED {
        ik (mA/cm2)
	ainf binf aexp bexp
	tau_b
}
 
BREAKPOINT {
        SOLVE deriv METHOD derivimplicit
        ik = gkAbar*a*b*(v - ek)
}
 
INITIAL {
	rates(v)
	a = ainf
	b = binf
}

DERIVATIVE deriv {  :Computes state variables m, h, and n rates(v)      
		: at the current v and dt.
		rates(v)		: fixes a bug in the original version 
        a' = (ainf - a)/(tau_a)
        b' = (binf - b)/(tau_b)
}
 
PROCEDURE rates(v) {  :Computes rate and other constants at current v.
                      :Call once from HOC to initialize inf at resting v.
        LOCAL alpha_b, beta_b
	TABLE ainf, aexp, binf, bexp, tau_a, tau_b  DEPEND dt, p FROM -200
TO 100 WITH 300
	alpha_b = 0.000009/exp((v-26)/18.5)
	beta_b = 0.014/(exp((v+70)/(-11))+0.2)
        ainf = 1/(1 + exp(-(v + 14)/16.6))
        aexp = 1 - exp(-dt/(tau_a))
	tau_b = 1/(alpha_b + beta_b)
        binf = 1/(1 + exp((v + 71)/7.3))
        bexp = 1 - exp(-dt/(tau_b))
}
 
UNITSON


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