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
                            
COMMENT

Ih current	 - hyperpolarization-activated nonspecific Na and K channel
		 - contributes to the resting membrane potential
		 - controls the afterhyperpolarization
Reference:

1.	Maccaferri, G. and McBain, C.J. The hyperpolarization-activated current
	(Ih) and its contribution to pacemaker activity in rat CA1 hippocampal
	stratum oriens-alveus interneurons, J. Physiol. 497.1:119-130,
	1996.

		V1/2 = -84.1 mV
		   k = 10.2
		reversal potential = -32.9 +/- 1.1 mV

at -70 mV, currents were fitted by a single exponetial of t = 2.8+/- 0.76 s
at -120 mV, two exponentials were required, t1 = 186.3+/-33.6 ms 
t2 = 1.04+/-0.16 s


2.	Maccaferri, G. et al. Properties of the
	Hyperpoarization-activated current in rat hippocampal CA1 Pyramidal
	cells. J. Neurophysiol. Vol. 69 No. 6:2129-2136, 1993.

		V1/2 = -97.9 mV
		   k = 13.4
		reversal potential = -18.3 mV

3.	Pape, H.C.  Queer current and pacemaker: The
	hyperpolarization-activated cation current in neurons, Annu. Rev. 
	Physiol. 58:299-327, 1996.

		single channel conductance is around 1 pS
		average channel density is below 0.5 um-2
		0.5 pS/um2 = 0.00005 mho/cm2 = 0.05 umho/cm2		
4.	Magee, J.C. Dendritic Hyperpolarization-Activated Currents Modify
	the Integrative Properties of Hippocampal CA1 Pyramidal Neurons, J.
	Neurosci., 18(19):7613-7624, 1998

Deals with Ih in CA1 pyramidal cells.  Finds that conductance density
increases with distance from the soma.

soma g = 0.0013846 mho/cm2
dendrite g (300-350 um away) = 0.0125 mho/cm2
see Table 1 in th paper

ENDCOMMENT

 UNITS {
        (mA) = (milliamp)
        (mV) = (millivolt)
}
 
NEURON {
        SUFFIX Ih
        USEION h READ eh WRITE ih VALENCE 1
        RANGE gkhbar,ih
        GLOBAL rinf, rexp, tau_r
}
 
INDEPENDENT {t FROM 0 TO 1 WITH 1 (ms)}
 
PARAMETER {
        v (mV)
        p = 5 (degC)
        dt (ms)
        gkhbar = 0.001385 (mho/cm2)			
        eh = -32.9 (mV)
}
 
STATE {
        r
}
 
ASSIGNED {
        ih (mA/cm2)
	rinf rexp
	tau_r
}
 
BREAKPOINT {
        SOLVE deriv METHOD derivimplicit
        ih = gkhbar*r*(v - eh)
}
 
INITIAL {
	rates(v)
	r = rinf
}

DERIVATIVE deriv { :Computes state variable h at current v and dt.
	rates(v)
	r' = (rinf - r)/tau_r
}

PROCEDURE rates(v) {  :Computes rate and other constants at current v.
                      :Call once from HOC to initialize inf at resting v.
        TABLE rinf, rexp, tau_r DEPEND dt, p FROM -200
TO 100 WITH 300
	rinf = 1/(1 + exp((v+84.1)/10.2))
	rexp = 1 - exp(-dt/(tau_r))
	tau_r = 100 + 1/(exp(-17.9-0.116*v)+exp(-1.84+0.09*v))
}
 
UNITSON


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