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 K-A channel from Klee Ficker and Heinemann
: modified by Brannon and Yiota Poirazi (poirazi@LNC.usc.edu) 
: to account for Hoffman et al 1997 distal region kinetics
: used only in locations > 100 microns from the soma
:
: modified to work with CVode by Carl Gold, 8/10/03
:  Updated by Maria Markaki  12/02/03

NEURON {
	SUFFIX kad
	USEION k READ ek WRITE ik
        RANGE gkabar,gka,ik,sh
        GLOBAL ninf,linf,taul,taun,lmin
}


UNITS {
	(mA) = (milliamp)
	(mV) = (millivolt)
}


PARAMETER {    :parameters that can be entered when function is called in cell-setup   
:	gkabar = 0.008  (mho/cm2)  :suggested conductance value
	gkabar = 0      (mho/cm2)  :initialized conductance
        vhalfn = -1     (mV)       :activation half-potential
        vhalfl = -56    (mV)       :inactivation half-potential
       a0n = 0.1       (/ms)      :parameters used
       : a0l = 0.05       (/ms)      :parameters used
        zetan = -1.8    (1)        :in calculation of
        zetal = 3       (1)        :steady state values
        gmn   = 0.39    (1)        :and time constants
        gml   = 1       (1)
	lmin  = 2       (ms)
	nmin  = 0.1     (ms)
:	nmin  = 0.2     (ms)	:suggested
	pw    = -1      (1)
	tq    = -40     (mV)
	qq    = 5       (mV)
	q10   = 5                :temperature sensitivity
     sh
}


ASSIGNED {    :parameters needed to solve DE
	v               (mV)
        ek              (mV)
	celsius  	(degC)
	ik              (mA/cm2)
        ninf
        linf      
        taul            (ms)
        taun            (ms)
        gka             (mho/cm2)
}


STATE {       :the unknown parameters to be solved in the DEs 
	n l
}

: Solve qt once in initial block
LOCAL qt

INITIAL {    :initialize the following parameter using rates()
      rates(v)
	n=ninf
	l=linf
}

BREAKPOINT {
	SOLVE states METHOD cnexp
      gka = gkabar*n*l
	ik = gka*(v-ek)
}


DERIVATIVE states {     : exact when v held constant; integrates over dt step
        rates(v)          : do this here
        n' = (ninf - n)/taun
        l' = (linf - l)/taul
}



PROCEDURE rates(v (mV)) {		 :callable from hoc
	LOCAL a,qt
        qt = q10^((celsius-24)/10)       : temprature adjastment factor
        a = alpn(v)
        ninf = 1/(1 + a)		 : activation variable steady state value
        taun = betn(v)/(qt*a0n*(1+a))	 : activation variable time constant
	if (taun<nmin) {taun=nmin}	 : time constant not allowed to be less than nmin

        a = alpl(v)
        linf = 1/(1+ a)                  : inactivation variable steady state value
	taul = 0.26(ms/mV)*(v+50)               : inactivation variable time constant
	if (taul<lmin) {taul=lmin}       : time constant not allowed to be less than lmin
}


FUNCTION alpn(v(mV)) { LOCAL zeta
  zeta = zetan+pw/(1+exp((v-tq-sh)/qq))
UNITSOFF
  alpn = exp(1.e-3*zeta*(v-vhalfn-sh)*9.648e4/(8.315*(273.16+celsius))) 
UNITSON
}

FUNCTION betn(v(mV)) { LOCAL zeta
  zeta = zetan+pw/(1+exp((v-tq-sh)/qq))
UNITSOFF
  betn = exp(1.e-3*zeta*gmn*(v-vhalfn-sh)*9.648e4/(8.315*(273.16+celsius))) 
UNITSON
}

FUNCTION alpl(v(mV)) {
UNITSOFF
  alpl = exp(1.e-3*zetal*(v-vhalfl-sh)*9.648e4/(8.315*(273.16+celsius))) 
UNITSON
}

FUNCTION betl(v(mV)) {
UNITSOFF
  betl = exp(1.e-3*zetal*gml*(v-vhalfl-sh)*9.648e4/(8.315*(273.16+celsius))) 
UNITSON
}