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 gskch.mod  calcium-activated potassium channel (non-voltage-dependent)

COMMENT

gsk granule

ENDCOMMENT

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

NEURON {
	SUFFIX gskch
	USEION sk READ esk WRITE isk VALENCE 1
	USEION nca READ ncai VALENCE 2
	USEION lca READ lcai VALENCE 2
	USEION tca READ tcai VALENCE 2
	RANGE gsk, gskbar, qinf, qtau, isk
}

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

PARAMETER {
	celsius=6.3 (degC)
	v		(mV)
	dt		(ms)
	gskbar  (mho/cm2)
	esk	(mV)
	cai (mM)
	ncai (mM)
	lcai (mM)
	tcai (mM)
}

STATE { q }

ASSIGNED {
	isk (mA/cm2) gsk (mho/cm2) qinf qtau (ms) qexp
}


BREAKPOINT {          :Computes i=g*q^2*(v-esk)
	SOLVE state
        gsk = gskbar * q*q
	isk = gsk * (v-esk)
}

UNITSOFF

INITIAL {
	cai = ncai + lcai + tcai	
	q=qinf
	rate(cai)
	VERBATIM
	ncai = _ion_ncai;
	lcai = _ion_lcai;
	tcai = _ion_tcai;
	ENDVERBATIM
}


PROCEDURE state() {  :Computes state variable q at current v and dt.
	cai = ncai + lcai + tcai
	rate(cai)
	q = q + (qinf-q) * qexp
	VERBATIM
	return 0;
	ENDVERBATIM
}

LOCAL q10
PROCEDURE rate(cai) {  :Computes rate and other constants at current v.
	LOCAL alpha, beta, tinc
	:q10 = 3^((celsius - 6.3)/10)
		:"q" activation system
	q10 = 1	: BPG
alpha = 1.25e1 * cai * cai
beta = 0.00025 

:	alpha = 0.00246/exp((12*log10(cai)+28.48)/-4.5)
:	beta = 0.006/exp((12*log10(cai)+60.4)/35)
: alpha = 0.00246/fctrap(cai)
: beta = 0.006/fctrap(cai)
	qtau = 1 / (alpha + beta)
	qinf = alpha * qtau
	tinc = -dt*q10
	qexp = 1 - exp(tinc/qtau)*q10
}

UNITSON

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