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, Lopes LV, Migliore M, Goutagny R, Bethus I, Marie H (2019) The Amyloid Precursor Protein C-terminal domain alters CA1 neuron firing, modifying hippocampus oscillations and impairing spatial memory encoding Cell Reports, in press
Citations  Citation Browser
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
                            
TITLE Ca R-type channel with medium threshold for activation
: used in distal dendritic regions, together with calH.mod, to help
: the generation of Ca++ spikes in these regions
: uses channel conductance (not permeability)
: written by Yiota Poirazi on 11/13/00 poirazi@LNC.usc.edu
:
: updated to use CVode by Carl Gold 08/10/03
:  Updated by Maria Markaki  03/12/03

NEURON {
	SUFFIX car
	USEION ca READ cai, cao WRITE ica
:	USEION Ca WRITE iCa VALENCE 2
        RANGE gcabar, m, h,ica
	RANGE inf, fac, tau
}

UNITS {
	(mA) = (milliamp)
	(mV) = (millivolt)
	(molar) = (1/liter)
	(mM) =	(millimolar)
	FARADAY = (faraday) (coulomb)
	R = (k-mole) (joule/degC)
}


ASSIGNED {               : parameters needed to solve DE
	ica (mA/cm2)
:	iCa (mA/cm2)
        inf[2]
	tau[2]		(ms)
        v               (mV)
        celsius 	(degC)
	   
	cai             (mM)      : initial internal Ca++ concentration
	cao             (mM)      : initial external Ca++ concentration
}


PARAMETER {              : parameters that can be entered when function is called in cell-setup
        gcabar = 0      (mho/cm2) : initialized conductance
        eca = 140       (mV)      : Ca++ reversal potential

       
}  

STATE {	
	m 
	h 
}            : unknown activation and inactivation parameters to be solved in the DEs  


INITIAL {
	rates(v)
        m = 0    : initial activation parameter value
	h = 1    : initial inactivation parameter value
}

BREAKPOINT {
	SOLVE states METHOD cnexp
	:ecar = (1e3) * (R*(celsius+273.15))/(2*FARADAY) * log (cao/cai)
	ica = gcabar*m*m*m*h*(v - eca)

}


DERIVATIVE states {
	rates(v)
	m' = (inf[0]-m)/tau[0]
	h' = (inf[1]-h)/tau[1]
}

PROCEDURE rates(v(mV)) {LOCAL a, b :rest = -70
	FROM i=0 TO 1 {
		tau[i] = vartau(v,i)
		inf[i] = varss(v,i)
	}
}




FUNCTION varss(v(mV), i) {
	if (i==0) {
	    varss = 1 / (1 + exp((v+48.5)/(-3(mV)))) : Ca activation
	}
	else if (i==1) {
             varss = 1/ (1 + exp((v+53)/(1(mV))))    : Ca inactivation
	}
}

FUNCTION vartau(v(mV), i) (ms){
	if (i==0) {
         vartau = 50(ms)  : activation variable time constant
   :       vartau = 120(ms)  : activation variable time constant
        }
	else if (i==1) {
          vartau = 5(ms)   : inactivation variable time constant
     :      vartau = 4(ms)   : inactivation variable time constant
       }
	
}