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
                            

{load_file("nrngui.hoc")}   // load the GUI and standard run libraries


//////////Parameters//////////////////////////
connect_random_low_start_ = 1

NCELL = 1      
n_simul=1  // number of simulations,

load_file("ranstream.hoc")
load_file("pyramidal_cell4b.hoc")
load_file("stim_cell.hoc")

cvode_active(1)



tstopI=200
tstop =tstopI+200
 

strdef str, flagname
str="HH"
celsius=34
flagname="Control"



redsAHP=1 
redmAHP=1 
tauca=3.6
thna3=-28
thna3dend=-28

somakap =0.007
somakad =0.007
somacaL=0.006// AD case 0.01   ctrl 0.006
ghsoma = 0.00004 
somacaT= 0.0007//  0.0004

shift=0
shiftkap=shift
shiftkad=shift
shifth=shift
shifth=shift

  


//********************************************
   
////////////////////


v_init=-65 // resting potential
///////////////////////

objref cells,ncstim[40],ranlist3,ranlist4,rs1,rs2,rs3,rs4,ncslist, nclist,ncc[40],ncslist2, nclist2,ncc2[100],ncstim2[100],rs,rs2

proc mkcells() {local i  localobj cell
  cells = new List()
	
  for i=0, $1-1 {

    cell = new PyramidalCell(redsAHP,redmAHP,v_init,tauca,thna3,thna3dend,somakap,somakad,ghsoma,somacaT,somacaL,shift)
    cells.append(cell)
		
  }
}


proc input(){

 mcell_ran4_init(1)

Nstim=20
Nstim2=20

rs = new RandomStream ($1*2+1)

for i=0, Nstim-1 {

 ncstim[i]  = new StimCell()	
    
             
 ncc[i]= ncstim[i].stim   //EC
 ncc[i].number = 100000
 ncc[i].start = 100
 ncc[i].interval = 25
 ncc[i].noise = 0.2
  ncc[i].noiseFromRandom(rs.r)
  rs.r.normal(0,1)
  rs.start()

   }


rs2 = new RandomStream ($1*2)


for i=0, Nstim2-1 {

   ncstim2[i]  = new StimCell()	 // CA3
  //ncstim2[i]  = new NetStim(.5)
  ncc2[i]= ncstim2[i].stim
  //ncc2[i]=ncstim2[i]
  ncc2[i].number = 100000
  ncc2[i].start = 100+9
  ncc2[i].interval = 25
  ncc2[i].noise = 0.2
   ncc2[i].noiseFromRandom(rs2.r)
  rs2.r.normal(0,1)
  rs2.start()
   }


}

ECW=0.001

proc connectcells() {local i,k,s,j localobj synE2,src,nc,ncs,synE

  ncslist = new List()
  nclist = new List()

 for i=0, cells.count-1 {  // iterating over sources
  for k=0, Nstim-1{                         
     src = ncstim[k].stim

   //src = ncstim[i]

  synE = cells.object(i).pre_list.object(0)
     nc = new NetCon(src, synE)
    nclist.append(nc)
    nc.delay = 1
    nc.weight =ECW

synE2 = cells.object(i).pre_list.object(1)
    ncs = new NetCon(src, synE2)
    ncslist.append(ncs)
    ncs.delay = 1
    ncs.weight =ECW


}

 } 
}

proc concells2() {local i,k,s,j localobj synE2,src2,nc2,ncs2,synE

  ncslist2 = new List()
  nclist2 = new List()

 for i=0, cells.count-1 {  // iterating over sources
    for k=0, Nstim2-1{                         
     src2 = ncstim2[k].stim
     //src2 = ncstim2[k]
     

  synE = cells.object(i).pre_list.object(23)
     synE.d=0*8/2
     synE.p=0*(1.2)/2 

     nc2 = new NetCon(src2, synE)
    nclist2.append(nc2)
    nc2.delay = 1
    nc2.weight =$1

synE2 = cells.object(i).pre_list.object(3)
    ncs2 = new NetCon(src2, synE2)
    ncslist2.append(ncs2)
    ncs2.delay = 1
    ncs2.weight =$2


}

 } 

}



//// Instrumentation, i.e. stimulation and recording////

objref apc, v1

proc insert_APC() {
apc = new APCount(0.5)
apc.thresh = -20
v1 = new Vector()
apc.record(v1)
}


objref clamp2

proc insert_IClamp2() {

     clamp2 = new IClamp(0.5)
     clamp2.del = 100
     clamp2.dur = tstopI
     clamp2.amp = $1
}




///////////////////////////////////////////////
objref tvec, idvec  // will be Vectors that record all spike times (tvec)
                   
proc spikerecord() {local i  localobj nc, nil
//  if ($1==0){
	  tvec = new Vector()
	  idvec = new Vector()
//	}
  for i=0, NCELL-1 {
    cells.object(i).soma nc=new NetCon(&v(1),nil,10,1,0.01)
    nc.record(tvec, idvec, i)
    // the Vector will continue to record spike times
    // even after the NetCon has been destroyed
  }
}

///////////////// currents /////

proc caT_insert() {
    
     for (x) if (x>0 && x<1)  {  
        xdist = distance(x)
       insert cat  
        if (xdist < 300) {
           gcatbar_cat(x) = $1*(1+xdist/60)

        } else {
           gcatbar_cat(x) = $1*6     
    }
}
}

proc caL_insert() {

     cal_distance=200
     for (x) if (x>0 && x<1) {  
         xdist = distance(x)
         insert calH
         mytau_calH=$2
         if (xdist < cal_distance) {
           gcalbar_calH(x) = $1 *(1-xdist/cal_distance)

        } else {
           gcalbar_calH(x) = 0       
    }

                    
     }
}

     

proc A_h_insert(){

     ghend=$1*7
     dhalf=280
     steep=50
     KMA=3
   
	insert h
        ghdbar_h=0
 	insert kap
   	  gkabar_kap = 0
	insert kad
   	 gkabar_kad = 0


	for (x) if (x>0 && x<1) {  
       	xdist=distance(x)

          	ghdbar_h(x)= $1 + (ghend - $1)/(1.0 + exp((dhalf-xdist)/steep))
             
     		 if (xdist < 100){
	         gkabar_kap(x) = $2*(1+KMA*xdist/100)
               vhalfl_h=-73

              	   }else{

                        vhalfl_h=-81
                       gkabar_kad(x) = $3*(1+KMA*xdist/100)
                      // print secname(), " ",xdist, gkabar_kad(x)
                 		         }
       

}
}


proc acc_dist(){local i

 for i=0, cells.count-1 {
     
      
       access cells.object(i).soma
       distance(0,x)

       access cells.object(i).radTprox
        A_h_insert(ghsoma,somakap,somakad)
        caT_insert(somacaT)
        caL_insert(somacaL,tauca)

     access cells.object(i).radTmed
        A_h_insert(ghsoma,somakap,somakad)
        caT_insert(somacaT)
         caL_insert(somacaL,tauca)

      access cells.object(i).radTdist
        A_h_insert(ghsoma,somakap,somakad)
        caT_insert(somacaT)
         caL_insert(somacaL,tauca)

 access cells.object(i).lm_thick1
        A_h_insert(ghsoma,somakap,somakad)
  access cells.object(i).lm_medium1
        A_h_insert(ghsoma,somakap,somakad)
 access cells.object(i).lm_thin1
        A_h_insert(ghsoma,somakap,somakad)

access cells.object(i).lm_thick2
        A_h_insert(ghsoma,somakap,somakad)
 access cells.object(i).lm_medium2
        A_h_insert(ghsoma,somakap,somakad)
 access cells.object(i).lm_thin2
        A_h_insert(ghsoma,somakap,somakad)
  


  }

}




/// Report simulation results-save potential and time////////////////////////

proc spikeout() { local i
  
printf("\ntime\t cell\n")
  for i=0, tvec.size-1 {
        printf("%g\t %d\n", tvec.x[i], idvec.x[i])
  }
}


objref rect, recv, listrecv

proc potential_record() {local i
  rect = new Vector()
  listrecv = new List()
  rect.record(&t)
  for i=0, cells.count-1 {
    recv = new Vector()
    recv.record(&cells.object(i).soma.v(0.5))
    listrecv.append(recv)
  }
}






/////////Main////////////////

  mkcells(NCELL)   

objref vec,vec_2,savdata3
strdef name3

 proc batchrun() { local i,k 
  sum=0
  sum_2=0
  mean=0
  mean_2=0
  SD=0
  vec=new Vector(n_simul)
  vec_2=new Vector(n_simul)

     for i=1,$1 {
		printf("\nRun %d\n", i)
		
	   run()
       	printf("//////Simulation: %d  ////// \n", i)
      
        printf("g: %f| # Spike: %d\n", $2, apc.n)

        //calculates mean and standard deviation

  
    vec.x[i-1]=apc.n
    vec_2.x[i-1]=(apc.n)^2
    temp=sum + vec.x[i-1]
    temp_2=sum_2 + vec_2.x[i-1]
    sum=temp
    sum_2=temp_2
  
	}   // end for i

   //////Mean and SD/////////

  mean = sum/n_simul
  mean_2 = sum_2/n_simul
  SD=sqrt(mean_2-mean^2)
  printf("___________________\n")
  printf("Mean: %lf\n", mean)
  printf("Std. Dev.: %lf\n", SD) 
  printf("___________________\n")

 
  if ($1==1) { savdata3.printf("%f \t %d\n",$2, apc.n)
              
       }else{ savdata3.printf("%.2f \t %.2f \t %.2f\n",$2*1000,mean,SD)
       }


}





acc_dist()


inizio=6
 for j=inizio,6{

   current=j*0.05
   access cells.object(0).soma
     
   
   insert_IClamp2(current)    
   insert_APC()
  
   cells.object(0).current_balance(v_init)



CWT=0.0004+j*0.00005
CNWT=0.00045



if (j==inizio){

      savdata3 = new File()

      sprint(name3,"Simulation_%s.dat",str)
      savdata3.wopen(name3)
      savdata3.printf("Current \t # Spikes\n")
       //savdata3.printf("g \t # Spikes \t SD\n")


   }


load_file("ses.ses")

batchrun(n_simul,current,CWT,CNWT)

 
} // for

savdata3.close()




//quit()













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