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 decay of internal calcium concentration
:
: Internal calcium concentration due to calcium currents and pump.
: Differential equations.
:
: Simple model of ATPase pump with 3 kinetic constants (Destexhe 92)
:     Cai + P <-> CaP -> Cao + P  (k1,k2,k3)
: A Michaelis-Menten approximation is assumed, which reduces the complexity
: of the system to 2 parameters: 
:       kt = <tot enzyme concentration> * k3  -> TIME CONSTANT OF THE PUMP
:	kd = k2/k1 (dissociation constant)    -> EQUILIBRIUM CALCIUM VALUE
: The values of these parameters are chosen assuming a high affinity of 
: the pump to calcium and a low transport capacity (cfr. Blaustein, 
: TINS, 11: 438, 1988, and references therein).  
:
: Units checked using "modlunit" -> factor 10000 needed in ca entry
:
: VERSION OF PUMP + DECAY (decay can be viewed as simplified buffering)
:
: All variables are range variables
:
:
: This mechanism was published in:  Destexhe, A. Babloyantz, A. and 
: Sejnowski, TJ.  Ionic mechanisms for intrinsic slow oscillations in
: thalamic relay neurons. Biophys. J. 65: 1538-1552, 1993)
:
: Written by Alain Destexhe, Salk Institute, Nov 12, 1992
:
: This file was modified by Yiota Poirazi (poirazi@LNC.usc.edu) on April 18, 2001 to account for the sharp
: Ca++ spike repolarization observed in: Golding, N. Jung H-Y., Mickus T. and Spruston N
: "Dendritic Calcium Spike Initiation and Repolarization are controlled by distinct potassium channel
: subtypes in CA1 pyramidal neurons". J. of Neuroscience 19(20) 8789-8798, 1999.
:
:  factor 10000 is replaced by 10000/18 needed in ca entry
:  taur --rate of calcium removal-- is replaced by taur*7 (7 times faster) 


INDEPENDENT {t FROM 0 TO 1 WITH 1 (ms)}

NEURON {
	SUFFIX cad
	USEION ca READ ica, cai WRITE cai	
        RANGE ca
	GLOBAL depth,cainf,taur
}

UNITS {
	(molar) = (1/liter)			: moles do not appear in units
	(mM)	= (millimolar)
	(um)	= (micron)
	(mA)	= (milliamp)
	(msM)	= (ms mM)
	FARADAY = (faraday) (coulomb)
}


PARAMETER {
	depth	= .1	(um)		: depth of shell
	taur	= 200	(ms)		: rate of calcium removal
	cainf	= 100e-6(mM)
	cai		(mM)
}

STATE {
	ca		(mM) 
}

INITIAL {
	ca = cainf
}

ASSIGNED {
	ica		(mA/cm2)
	drive_channel	(mM/ms)
}
	
BREAKPOINT {
	SOLVE state METHOD cnexp
}

DERIVATIVE state { 

	drive_channel =  - (10000) * ica / (2 * FARADAY * depth)
	if (drive_channel <= 0.) { drive_channel = 0.  }   : cannot pump inward 
         
	ca' = drive_channel/18 + (cainf-ca)/(taur*7)
      : ca' = drive_channel/20 + (cainf -ca)/(taur*9)
       
  

	cai = ca
}







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