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
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 Slow Ca-dependent potassium current
                            :
                            :   Ca++ dependent K+ current IC responsible for slow AHP
                            :   Differential equations
                            :
                            :   Model based on a first order kinetic scheme
                            :
                            :       + n cai <->     (alpha,beta)
                            :
                            :   Following this model, the activation fct will be half-activated at 
                            :   a concentration of Cai = (beta/alpha)^(1/n) = cac (parameter)
                            :
                            :   The mod file is here written for the case n=2 (2 binding sites)
                            :   ---------------------------------------------
                            :
                            :   This current models the "slow" IK[Ca] (IAHP): 
                            :      - potassium current
                            :      - activated by intracellular calcium
                            :      - NOT voltage dependent
                            :
                            :   A minimal value for the time constant has been added
                            :
                            :   Ref: Destexhe et al., J. Neurophysiology 72: 803-818, 1994.
                            :   See also: http://www.cnl.salk.edu/~alain , http://cns.fmed.ulaval.ca
                            :   modifications by Yiota Poirazi 2001 (poirazi@LNC.usc.edu)
			    :   taumin = 0.5 ms instead of 0.1 ms	

                            NEURON {
                                    SUFFIX kca
                                    USEION k READ ek WRITE ik
                                    USEION ca READ cai
                                    RANGE gk, gbar, m_inf, tau_m,ik
                                    GLOBAL beta, cac
                            }


                            UNITS {
                                    (mA) = (milliamp)
                                    (mV) = (millivolt)
                                    (molar) = (1/liter)
                                    (mM) = (millimolar)
                            }


                            PARAMETER {
                                    v               (mV)
                                    celsius = 36    (degC)
                                    ek      = -80   (mV)
                                    cai     = 2.4e-5 (mM)           : initial [Ca]i
                                    gbar    = 0.01   (mho/cm2)
                                    beta    = 0.03   (1/ms)          : backward rate constant
                                    cac     = 0.025  (mM)            : middle point of activation fct
       				    taumin  = 0.5    (ms)            : minimal value of the time cst
                                    gk
                                  }


                            STATE {m}        : activation variable to be solved in the DEs       

                            ASSIGNED {       : parameters needed to solve DE 
                                    ik      (mA/cm2)
                                    m_inf
                                    tau_m   (ms)
                                    tadj
                            }
                            BREAKPOINT { 
                                    SOLVE states METHOD derivimplicit
                                    gk = gbar*m*m*m     : maximum channel conductance
                                    ik = gk*(v - ek)    : potassium current induced by this channel
                            }

                            DERIVATIVE states { 
                                    evaluate_fct(v,cai)
                                    m' = (m_inf - m) / tau_m
                            }

                            UNITSOFF
                            INITIAL {
                            :
                            :  activation kinetics are assumed to be at 22 deg. C
                            :  Q10 is assumed to be 3
                            :
                                    tadj = 3 ^ ((celsius-22.0)/10) : temperature-dependent adjastment factor
                                    evaluate_fct(v,cai)
                                    m = m_inf
                            }

                            PROCEDURE evaluate_fct(v(mV),cai(mM)) {  LOCAL car
                                    car = (cai/cac)^2
                                    m_inf = car / ( 1 + car )      : activation steady state value
                                    tau_m =  1 / beta / (1 + car) / tadj
                                    if(tau_m < taumin) { tau_m = taumin }   : activation min value of time cst
                            }
                            UNITSON

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