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
Citations  Citation Browser
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
                            
: STDP by Hines, changed to dual exponential (BPG 6-1-09)
: Modified by BPG 13-12-08
: Limited weights: max weight is wmax and min weight is wmin
: (initial weight is specified by netconn - usually set to wmin)
: Rhythmic GABAB suppresses conductance and promotes plasticity.
: When GABAB is low, conductance is high and plasticity is off.

NEURON {
	POINT_PROCESS STDPE2
	RANGE tau1, tau2, e, i, d, p, dtau, ptau, thresh, wmax, wmin
	RANGE g, gbdel, gblen, gbint, gscale, factor,dM,dV,B,C
	NONSPECIFIC_CURRENT i
}

UNITS {
	(nA) = (nanoamp)
	(mV) = (millivolt)
	(uS) = (microsiemens)
}

PARAMETER {
	tau1=.1 (ms) <1e-9,1e9>
	tau2 = 10 (ms) <1e-9,1e9>
	e = 0	(mV)
     pi=3.14159
	wmax = 0.0015 (uS)
      :wmax = 0.005 (uS)
	wmin = 0.0005 (uS)	: not used - use netconn weight instead (BPG)
	d = 8 : depression factor (multiplicative to prevent < 0)
	p = 1.2 : potentiation factor (additive, non-saturating)
	
       dM = -22   (ms)
       dV= 5    (ms)
	 ptau = 10 (ms) : Nishiyama2000

	:thresh = -20 (mV)	: postsynaptic voltage threshold
      thresh = -55 (mV)	: postsynaptic voltage threshold
	gbdel = 50 (ms) <1e-9,1e9> : initial GABAB off interval (ms)
	gbint = 125 (ms) <1e-9,1e9> : GABAB off interval (ms)
	gblen = 125 (ms) <1e-9,1e9> : GABAB on length (ms)
	gscale = 0.4	: relative suppression by GABAB
      
}

ASSIGNED {
	v (mV)
	i (nA)
	tpost (ms)
	on
	g (uS)
	gs
	factor
}

STATE {
	C (uS)
	B (uS)
}

INITIAL {
	LOCAL tp
	if (tau1/tau2 > .9999) {
		tau1 = .9999*tau2
	}
	C = 0
	B = 0
	tp = (tau1*tau2)/(tau2 - tau1) * log(tau2/tau1)
	factor = -exp(-tp/tau1) + exp(-tp/tau2)
	factor = 1/factor    
	gs=1
	on=0	: initially not plastic
	tpost = -1e9
	net_send(0, 1)
	net_send(gbdel, 3)	: initial GABAB off period
}

BREAKPOINT {
	SOLVE state METHOD cnexp
	g = B - C
     	i = g*gs*(v - e)
    
}

DERIVATIVE state {
	C' = -C/tau1
	B' = -B/tau2
}

NET_RECEIVE(w (uS), A, tpre (ms) ) {
	INITIAL { A = 0  tpre = -1e9 }
	if (flag == 0) { : presynaptic spike  (after last post so depress)
	:	printf("entry flag=%g t=%g w=%g A=%g tpre=%g tpost=%g\n", flag, t, w, A, tpre, tpost)
:		g = g + w + A	: only for single exp (BPG)
		C = C + (w + A)*factor
		B = B + (w + A)*factor
          	:printf(" B %f\t C %f\t w %f\n",B, C, w)
		tpre = t
		if (on == 1) {
			A = A * (1-(d*exp(-((tpost-t)-dM)^2/(2*dV*dV))) /(sqrt(2*pi)*dV))
		}
	}else if (flag == 2 && on == 1) { : postsynaptic spike
:		printf("entry flag=%g t=%g tpost=%g\n", flag, t, tpost)
		tpost = t
            FOR_NETCONS(w1, A1, tp) { : also can hide NET_RECEIVE args
			:printf("entry FOR_NETCONS w1=%g A1=%g tp=%g t=%g\n", w1, A1, tp, t)
			A1 = A1 + (wmax-w1-A1)*p*exp((tp - t)/ptau)
			}
	} else if (flag == 1) { : flag == 1 from INITIAL block
:		printf("entry flag=%g t=%g\n", flag, t)
		WATCH (v > thresh) 2
	}
	else if (flag == 3) { : plasticity control
		if (on == 0) { : start plasticity
			on = 1
			gs = gscale
			net_send(gblen, 3)
		}
		else { : end burst
			on = 0
			gs = 1
			net_send(gbint, 3)
		}
	}
}