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, Goutagny R, Bethus I, Lopes LV, Migliore M, Marie H (2019) The Amyloid Precursor Protein C-Terminal Domain Alters CA1 Neuron Firing, Modifying Hippocampus Oscillations and Impairing Spatial Memory Encoding. Cell Rep 29:317-331.e5 [PubMed]
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
                            
COMMENT

Sodium current for the dendrites

References:

1.	Martina, M., Vida, I., and Jonas, P.  Distal initiation and active
	propagation of action potentials in interneuron dendrites,
	Science, 287:295-300, 2000.

			soma	axon-lacking dend	axon-bearing dend
Na+	gmax	    107 ps/um2	   117 ps/um2		   107 ps/um2
	slope 	    10.9 mV/e	   11.2 mV/e		   11.2 mV/e
	V1/2        -37.8 mV       -45.6 mV                -45.6 mV



2.	Marina, M. and Jonas, P.  Functional differences in Na+ channel
	gating between fast-spiking interneurons and principal neurones of rat
	hippocampus, J. Physiol., 505.3:593-603, 1997.

*Note* The interneurons here are basket cells from the dentate gyrus.

Na+	Activation V1/2				-25.1 mV
	slope			 		11.5
	Activation t (-20 mV)	 		0.16 ms
	Deactivation t (-40 mV)	 		0.13 ms
 	Inactivation V1/2			-58.3 mV
	slope			 		6.7
	onset of inactivation t (-20 mV)	1.34 ms
	onset of inactivation t (-55 mV)	18.6 ms
	recovery from inactivation t		2.0 ms
	(30 ms conditioning pulse)
	recovery from inactivation t		2.7 ms
	(300 ms conditioning pulse)

ENDCOMMENT
UNITS {
        (mA) = (milliamp)
        (mV) = (millivolt)
}
 
NEURON {
        SUFFIX Nadend
        USEION na READ ena WRITE ina
        NONSPECIFIC_CURRENT il
        RANGE gnadend, gl, el, ina
        GLOBAL minf, hinf, hexp, mtau, htau
}
 
INDEPENDENT {t FROM 0 TO 1 WITH 1 (ms)}
 
PARAMETER {
        v (mV)
        celsius = 24 (degC)
        dt (ms)
        gnadend = .0117 (mho/cm2)
        ena = 90 (mV)
        gl = .00005 (mho/cm2)
        el = -70 (mV)
}
 
STATE {
        m h 
}
 
ASSIGNED {
        ina (mA/cm2)
        il (mA/cm2)
        minf 
	mexp 
	hinf 
	hexp
	mtau (ms)
	htau (ms)
}
 
INITIAL {
	m = minf
	h = hinf
}

BREAKPOINT {
        SOLVE states
	ina = gnadend*minf*minf*minf*h*(v - ena)    
        il = gl*(v - el)
}

PROCEDURE states() {	:exact when v held constant
	evaluate_fct(v)
	h = h + hexp*(hinf - h)
	VERBATIM
	return 0;
	ENDVERBATIM 
}
UNITSOFF

PROCEDURE evaluate_fct(v(mV)) {  :Computes rate and other constants at 
		      :current v.
                      :Call once from HOC to initialize inf at resting v.
        LOCAL q10, tinc, alpha, beta
        TABLE minf, hinf, hexp, mtau, htau DEPEND dt, celsius FROM -200 TO 
100 WITH 300
:		q10 = 3^((celsius - 24)/10)
		q10 = 1	: BPG
		tinc = -dt*q10
		alpha = 0.1*vtrap(-(v+45),10)
		beta = 4*exp(-(v+70)/18)
		mtau = 1/(alpha + beta)
		minf = alpha*mtau
		alpha = 0.07*Exp(-(v+70)/20)
		beta = 1/(1+Exp(-(v+40)/10))
		htau = 1/(alpha + beta)
		hinf = alpha*htau
		hexp = 1-Exp(tinc/htau)
}
FUNCTION vtrap(x,y) {	:Traps for 0 in denominator of rate eqns.
		if (fabs(x/y) < 1e-6) {
			vtrap = y*(1 - x/y/2)
		}else{
			vtrap = x/(Exp(x/y) - 1)
		}
}
FUNCTION Exp(x) {
		if (x < -100) {
			Exp = 0
		}else{
			Exp = exp(x)
		}
}
UNITSON

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