Effects of increasing CREB on storage and recall processes in a CA1 network (Bianchi et al. 2014)

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Accession:151126
Several recent results suggest that boosting the CREB pathway improves hippocampal-dependent memory in healthy rodents and restores this type of memory in an AD mouse model. However, not much is known about how CREB-dependent neuronal alterations in synaptic strength, excitability and LTP can boost memory formation in the complex architecture of a neuronal network. Using a model of a CA1 microcircuit, we investigate whether hippocampal CA1 pyramidal neuron properties altered by increasing CREB activity may contribute to improve memory storage and recall. With a set of patterns presented to a network, we find that the pattern recall quality under AD-like conditions is significantly better when boosting CREB function with respect to control. The results are robust and consistent upon increasing the synaptic damage expected by AD progression, supporting the idea that the use of CREB-based therapies could provide a new approach to treat AD.
Reference:
1 . Bianchi D, De Michele P, Marchetti C, Tirozzi B, Cuomo S, Marie H, Migliore M (2014) Effects of increasing CREB-dependent transcription on the storage and recall processes in a hippocampal CA1 microcircuit. Hippocampus 24:165-77 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Realistic Network;
Brain Region(s)/Organism:
Cell Type(s): Hippocampus CA1 pyramidal cell; Hippocampus CA1 interneuron oriens alveus cell; Hippocampus CA1 basket cell;
Channel(s): I Na,t; I A; I K; I M; I h; I K,Ca; I Calcium; I_AHP; I Cl, leak; Ca pump;
Gap Junctions:
Receptor(s): GabaA; GabaB; AMPA; NMDA;
Gene(s):
Transmitter(s): Gaba; Glutamate;
Simulation Environment: NEURON;
Model Concept(s): STDP; Aging/Alzheimer`s; Depolarization block; Storage/recall; CREB;
Implementer(s): Bianchi, Daniela [danielabianchi12 -at- gmail.com]; De Michele, Pasquale [pasquale.demichele at unina.it];
Search NeuronDB for information about:  Hippocampus CA1 pyramidal cell; Hippocampus CA1 interneuron oriens alveus cell; GabaA; GabaB; AMPA; NMDA; I Na,t; I A; I K; I M; I h; I K,Ca; I Calcium; I_AHP; I Cl, leak; Ca pump; Gaba; Glutamate;
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Bianchietal
Results
Weights
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
axoaxonic_cell17S.hoc *
basket_cell17S.hoc *
bistratified_cell13S.hoc *
burst_cell.hoc *
HAM_SR1.ses
mosinit.hoc
olm_cell2.hoc
PureRec_phase.hoc
PureRec_phase_ser.hoc
pyramidal_cell4.hoc
ranstream.hoc *
stim_cell.hoc
Sto_phase.hoc
Sto_phase_ser.hoc
                            
TITLE na3
: Na current 
: from Jeff M.
:  ---------- modified -------M.Migliore may97

NEURON {
	SUFFIX na3notrunk
	USEION na READ ena WRITE ina
	RANGE  gbar, ar2,tha
	GLOBAL minf, hinf, mtau, htau, sinf, taus,qinf, thinf
}

PARAMETER {
	gbar = 0.010   	(mho/cm2)	
							
	tha  =  -23  (mV)		: v 1/2 for act	
	qa   = 7.2	(mV)		: act slope (4.5)		
	Ra   = 0.4	(/ms)		: open (v)		
	Rb   = 0.124 	(/ms)		: close (v)		

	thi1  = -45	(mV)		: v 1/2 for inact 	
	thi2  = -45 	(mV)		: v 1/2 for inact 	
	qd   = 1.5	(mV)	        : inact tau slope
	qg   = 1.5      (mV)
	mmin=0.02	
	hmin=0.5			
	q10=3
	Rg   = 0.01 	(/ms)		: inact recov (v) 	
	Rd   = .03 	(/ms)		: inact (v)	
	qq   = 10        (mV)
	tq   = -55      (mV)

	thinf  = -50	(mV)		: inact inf slope	
	qinf  = 2	(mV)		: inact inf slope 

        vhalfs=-60	(mV)		: slow inact.
        a0s=0.0003	(ms)		: a0s=b0s
        zetas=12	(1)
        gms=0.2		(1)
        smax=10		(ms)
        vvh=-58		(mV) 
        vvs=2		(mV)
        ar2=1		(1)		: 1=no inact., 0=max inact.
	ena		(mV)            : must be explicitly def. in hoc
	celsius
	v 		(mV)
}


UNITS {
	(mA) = (milliamp)
	(mV) = (millivolt)
	(pS) = (picosiemens)
	(um) = (micron)
} 

ASSIGNED {
	ina 		(mA/cm2)
	thegna		(mho/cm2)
	minf 		hinf 		
	mtau (ms)	htau (ms) 	
	sinf (ms)	taus (ms)
}
 

STATE { m h s}

BREAKPOINT {
        SOLVE states METHOD cnexp
        thegna = gbar*m*m*m*h*s
	ina = thegna * (v - ena)
} 

INITIAL {
	trates(v,ar2)
	m=minf  
	h=hinf
	s=sinf
}


FUNCTION alpv(v(mV)) {
         alpv = 1/(1+exp((v-vvh)/vvs))
}
        
FUNCTION alps(v(mV)) {  
  alps = exp(1.e-3*zetas*(v-vhalfs)*9.648e4/(8.315*(273.16+celsius)))
}

FUNCTION bets(v(mV)) {
  bets = exp(1.e-3*zetas*gms*(v-vhalfs)*9.648e4/(8.315*(273.16+celsius)))
}

LOCAL mexp, hexp, sexp

DERIVATIVE states {   
        trates(v,ar2)      
        m' = (minf-m)/mtau
        h' = (hinf-h)/htau
        s' = (sinf - s)/taus
}

PROCEDURE trates(vm,a2) {  
        LOCAL  a, b, c, qt
        qt=q10^((celsius-24)/10)
	a = trap0(vm,tha,Ra,qa)
	b = trap0(-vm,-tha,Rb,qa)
	mtau = 1/(a+b)/qt
        if (mtau<mmin) {mtau=mmin}
	minf = a/(a+b)

	a = trap0(vm,thi1,Rd,qd)
	b = trap0(-vm,-thi2,Rg,qg)
	htau =  1/(a+b)/qt
        if (htau<hmin) {htau=hmin}
	hinf = 1/(1+exp((vm-thinf)/qinf))
	c=alpv(vm)
        sinf = c+a2*(1-c)
        taus = bets(vm)/(a0s*(1+alps(vm)))
        if (taus<smax) {taus=smax}
}

FUNCTION trap0(v,th,a,q) {
	if (fabs(v-th) > 1e-6) {
	        trap0 = a * (v - th) / (1 - exp(-(v - th)/q))
	} else {
	        trap0 = a * q
 	}
}	

        


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