Coincident glutamatergic depolarization effects on Cl- dynamics (Lombardi et al, 2021)

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Accession:266823
"... we used compartmental biophysical models of Cl- dynamics simulating either a simple ball-and-stick topology or a reconstructed CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl- influx at low and attenuates or reverses the Cl- efflux at high initial [Cl-]i. The size of glutamatergic influence on GABAergic Cl--fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl--fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval..."
Reference:
1 . Lombardi A, Jedlicka P, Luhmann HJ, Kilb W (2021) Coincident glutamatergic depolarizations enhance GABAA receptor-dependent Cl- influx in mature and suppress Cl- efflux in immature neurons PLOS Comp Bio
Model Information (Click on a link to find other models with that property)
Model Type: Synapse; Dendrite;
Brain Region(s)/Organism:
Cell Type(s): Hippocampus CA3 pyramidal GLU cell;
Channel(s):
Gap Junctions:
Receptor(s): GabaA; AMPA; NMDA;
Gene(s):
Transmitter(s): Gaba; Glutamate;
Simulation Environment: NEURON;
Model Concept(s): Short-term Synaptic Plasticity; Synaptic Plasticity; Chloride regulation;
Implementer(s): Jedlicka, Peter [jedlicka at em.uni-frankfurt.de]; Kilb, Werner [wkilb at uni-mainz.de];
Search NeuronDB for information about:  Hippocampus CA3 pyramidal GLU cell; GabaA; AMPA; NMDA; Gaba; Glutamate;
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_For Zip -Neuron-Models_AMPA-GABA
Fig3a-d_Ball-Stick_var-tauAMPA
cldif_CA3_NKCC1_HCO3.mod *
gabaA_Cl_HCO3.mod *
vecevent.mod *
cell_soma_dendrite.hoc *
GABA-AMPA_BS_var-tauAMPA_Var-Cl.hoc
GABA-AMPA_BS_var-tauAMPA_Var-Cl_gAMPAx10.hoc
init_Cldif.hoc *
Isolated_Dendrite.ses *
start_GABA-AMPA_BS_Var-tauAMPA_Var-Cl.hoc
start_GABA-AMPA_BS_Var-tauAMPA_Var-Cl_gAMPA-x10.hoc
                            
// Simulation and analysis of Spatiotemporal Component of Cl- Gradients in a isolated dendrite
// Here simulation of different AMPA Synapses
// Here application in a simple Ball and Stick Model

// Define spatial properties of dendrite
  ANZAHL_NODES = 100

// Define number or Repetitions of the non-Cl-Parameter
  MAX_FAKTOR = 100          //Number of repetitions

// Define Cl--Concentration
   Cl_Steps = 6  // Number of Different [Cl-]i  
   objref Cl_List
   Cl_List = new Vector(Cl_Steps)
   Cl_List.x[0] = 5 //mM
   Cl_List.x[1] = 10
   Cl_List.x[2] = 15
   Cl_List.x[3] = 25
   Cl_List.x[4] = 35
   Cl_List.x[5] = 50

// Determination Parameters GABA
  ANZAHL_GABA = 1           //Anzahl der synaptischen Pulse
  G_GABA = 0.000789         //Value from Lombardi et al 2018 
  P_GABA = 0.18
  DECAY_GABA = 37           //Value from Lombardi et al 2018
  GABA_SYN_LOCATION = 0.5   // Position GABA Synapse for Pulses
  ONSET_GABA_PULSE = 10  

// Determination Parameters AMPA
  ANZAHL_AMPA = 1                   //Anzahl der synaptischen Pulse
  G_AMPA = 0.000305 * 1             //Value from Lombardi et al 2018 
  E_AMPA = 0                        // Reversal Potential of Exp2Syn
  DECAY_AMPA = 11                   //Value from Lombardi et al 2018
  Decay_Ampa_0 = 0
  AMPA_SYN_LOCATION = 0.5   // Position GABA Synapse for Pulses
  ONSET_AMPA_PULSE = 10  

// Identification of the node with the GABA Synapse
  SynPos = ANZAHL_NODES*GABA_SYN_LOCATION

//----- Define run parameters ---------------------
  tstop = 200   // Duration
  v_init = -60   // Initial voltage
  dt = 0.5      // Step Interval in ms
  lenghtoutputvec = 2000                   // Number of Lines for output (< 32000 for Excel-Figures)

//-- Initialize Graph for Display of [Cli]i in the right scale
objectvar Cl_graph
Cl_graph = new Graph(0)
Cl_graph.size(0,210,10,50)
Cl_graph.view(0, 10, 210, 40, 462, 636, 961.2, 200.8)
graphList[0].append(Cl_graph)
Cl_graph.addexpr("dend.cli( 0.5 )", 1, 1, 0.8, 0.9, 2)

//----- Insert synapses -------------------------
// Determination of GABA Synapse
  objref gabasyn
  dend {
    // insert GABA synapse 
    gabasyn = new gaba(GABA_SYN_LOCATION)
    gabasyn.tau1 = 0.1 
    gabasyn.tau2 = DECAY_GABA
    gabasyn.P = P_GABA
  }

// Definition of synaptic Stimuli
  objref stimGABApuls //Pulssequenz GABA
  stimGABApuls = new NetStim(GABA_SYN_LOCATION)
  stimGABApuls.number = ANZAHL_GABA
  stimGABApuls.start = ONSET_GABA_PULSE

// Linkage of synaptic Inputs
  objref synpulsegaba

// Determination of AMPA Synapse
  objref ampasyn
  dend {
    // insert AMPA synapse 
    ampasyn = new Exp2Syn(AMPA_SYN_LOCATION)
    ampasyn.tau1 = 0.1 
    ampasyn.tau2 = Decay_Ampa_0
    ampasyn.e = E_AMPA
  }

// Definition of synaptic Stimuli
  objref stimAMPApuls //Pulssequenz AMPA
  stimAMPApuls = new NetStim(AMPA_SYN_LOCATION)
  stimAMPApuls.number = ANZAHL_AMPA
  stimAMPApuls.start = ONSET_AMPA_PULSE

// Linkage of synaptic Inputs
  objref synpulseampa



// ------------Procedures and Functions -------------------------------
// --------------------------------------------------------------------

// Function MakeShort ---------------------------------------//
// Inputs: $1 Objref to Inputvector                          //
//         $2 Objref to Outoutvector                         //
//         lenoutvec  desired lendth of Outputvector         //
//                                                           //
// Reduce Inputvec to Outputvev by averaging n elements      //
// n (reducing factor) = floor(Inputvec.size() / lenoutvec)  //
// ----------------------------------------------------------//

obfunc MakeShort() {local i, n

  n = int($o1.size()/$3)
  $o2.resize($3)
  for i=0, $3-1 {
    $o2.x[i] = $o1.mean(i*n, (i+1)*n-1)
  }
  return $o2
}   //  End of function


// ---------Definition of Output Vectors and File Output --------------
// --------------------------------------------------------------------

//-- Define  ------
  objref timevec, shorttimevec
  objref voltvec[ANZAHL_NODES], shortvoltvec, voltvec_aver
  objref clivec[ANZAHL_NODES], shortclivec, clivec_aver
  objref Outmatrix  //0=time, FAKTOR=Cl-, MAX_FAKTOR+FAKTOR = v
  objref Analysismatrix //0=[Cl-]-initial, 1=gAMPA, 2=[Cl-]max, 3=[Cl-]min, 4=vmax, 5=vmin

  strdef OutFileName                       // Name of File Output
  objref OutFile 

//--- Assign -------
  timevec = new Vector()
  shorttimevec = new Vector()
  for i = 0, ANZAHL_NODES-1 {    
     voltvec[i] = new Vector()
     clivec[i] = new Vector()
  }
// not used in thie simulation  clivec_aver = new Vector()
// not used in thie simulation  voltvec_aver = new Vector()
  shortclivec = new Vector()
  shortvoltvec = new Vector()
  Outmatrix = new Matrix()
  Analysismatrix = new Matrix(6, MAX_FAKTOR*Cl_Steps+1)


//-- Link Output Vectors ----------------
  timevec.record(&t)                          // Time vector
  for i = 0, ANZAHL_NODES-1 {                 // Generate Vektor for each node
    voltvec[i].record(&dend.v(i/ANZAHL_NODES))    
    clivec[i].record(&dend.cli(i/ANZAHL_NODES))
  }

// --- Simulation starts here ------------------------------------------------------------------------------
// ---------------------------------------------------------------------------------------------------------

//-- Outer Loop Variation of [Cli] initial -------------------
  Cl_Step = 0
  while (Cl_Step < Cl_Steps){

    // Update Cl- homeostasis in all compartments ----------------------------------------------
    forsec all {
      cli0_cldif_CA3_NKCC1_HCO3 = Cl_List.x[Cl_Step]
      cli_Start_cldif_CA3_NKCC1_HCO3 = Cl_List.x[Cl_Step]
      cli_cldif_CA3_NKCC1_HCO3 = Cl_List.x[Cl_Step]
    }
//-- Inner Loop Variation of g-AMPA --------------------------------------------------------------

      FAKTOR_DECAY_AMPA = 0
      DECAY_AMPA = Decay_Ampa_0
      while (FAKTOR_DECAY_AMPA < MAX_FAKTOR) {

      // Assign Value to Synapse
      dend {
            synpulsegaba = new NetCon(stimGABApuls, gabasyn, 0, 0, G_GABA)
            ampasyn.tau2 = DECAY_AMPA
            if (DECAY_AMPA == 0){            
               ampasyn.tau2 = 11
               synpulseampa = new NetCon(stimAMPApuls, ampasyn, 0, 0, 0)
            }else{
               synpulseampa = new NetCon(stimAMPApuls, ampasyn, 0, 0, G_AMPA)
            }
      }

      printf("Faktor = %g of %g ", Cl_Step*MAX_FAKTOR+FAKTOR_DECAY_AMPA+1, MAX_FAKTOR*Cl_Steps)
      Cl_graph.size(0, tstop, Cl_List.x[Cl_Step]- 1, Cl_List.x[Cl_Step] + 1)

      // Run Simulation --------------------------------------------------------
         run()
      // Put Data in Output Matrix --------------------------------------------
      // ---- => shrink the parameters to output-size before ---------------------
       MakeShort(timevec, shorttimevec, lenghtoutputvec)   
       Outmatrix.resize(shorttimevec.size(), 1 + 2 * MAX_FAKTOR)
       Outmatrix.setcol(0, shorttimevec)
   
                                            // Not used for this analysis  // Calculate average [Cli] over all Nodes -------
                                            //   clivec_aver.resize(clivec[0].size())
                                            //   voltvec_aver.resize(voltvec[0].size())
                                            //   clivec_aver.mul(0)                      // empty vector
                                            //   voltvec_aver.mul(0) 
                                            //   for i=0, ANZAHL_NODES-1 {
                                            //        clivec_aver.add(clivec[i])
                                            //        voltvec_aver.add(voltvec[i])
                                            //    } 
                                            //    clivec_aver.div(ANZAHL_NODES)
                                            //    voltvec_aver.div(ANZAHL_NODES)
        //  determine delta CLi
        if (abs(clivec[SynPos].x[1]-clivec[SynPos].min()) > abs(clivec[SynPos].x[1]-clivec[SynPos].max())){
           DeltaCl = clivec[SynPos].min()- clivec[SynPos].x[1]
        }else{
           DeltaCl = clivec[SynPos].max() -clivec[SynPos].x[1]
        }
        printf("- dec_AMPA = %g ms - [Cl-]i = %g mM => Delta[Cl-]i = %g mM, Em = %g mV \n", DECAY_AMPA, Cl_List.x[Cl_Step], DeltaCl, voltvec[SynPos].max())

        // Put Vectors in Outmatrix 
        MakeShort(clivec[SynPos], shortclivec, lenghtoutputvec)   
        MakeShort(voltvec[SynPos], shortvoltvec, lenghtoutputvec)
        shortclivec.x[0] = DECAY_AMPA
        shortvoltvec.x[0] = DECAY_AMPA
        Outmatrix.setcol(FAKTOR_DECAY_AMPA, shortclivec)
        Outmatrix.setcol(MAX_FAKTOR + FAKTOR_DECAY_AMPA, shortvoltvec)
        Analysismatrix.x[0][Cl_Step*MAX_FAKTOR+FAKTOR_DECAY_AMPA] = Cl_List.x[Cl_Step]
        Analysismatrix.x[1][Cl_Step*MAX_FAKTOR+FAKTOR_DECAY_AMPA] = DECAY_AMPA
        Analysismatrix.x[2][Cl_Step*MAX_FAKTOR+FAKTOR_DECAY_AMPA] = clivec[SynPos].max()
        Analysismatrix.x[3][Cl_Step*MAX_FAKTOR+FAKTOR_DECAY_AMPA] = clivec[SynPos].min()
        Analysismatrix.x[4][Cl_Step*MAX_FAKTOR+FAKTOR_DECAY_AMPA] = voltvec[SynPos].max()
        Analysismatrix.x[5][Cl_Step*MAX_FAKTOR+FAKTOR_DECAY_AMPA] = voltvec[SynPos].min()
        // Goto next FAKTOR_DECAY_AMPA
        FAKTOR_DECAY_AMPA+=1
        DECAY_AMPA+= 1
     }
     // ----- end of inner loop (FAKTOR_DECAY_AMPA-Loop) -------

     // Save the Data --------------------------------------------------------------------
     OutFile = new File()
     sprint(OutFileName, "Result_BS_Cli-%gmM_Var-tauAMPA_gAMPA.asc", Cl_List.x[Cl_Step])
     OutFile.wopen(OutFileName) 
     Outmatrix.fprint(OutFile, "\t%g")     
     OutFile.close
   // Goto next Cl- Concentration
   Cl_Step+=1
   DECAY_AMPA = Decay_Ampa_0
} 
// ---------- End of outer loop  (Cl_Step-Loop) ----------------------

// Save the Analysismatrix  --------------------------------------------------------------------
  OutFile = new File()
  sprint(OutFileName, "Analysis_BS_Var-Cli_Var-tauAMPA_5u10mM_gAMPA.asc")
  OutFile.wopen(OutFileName) 
  Analysismatrix.fprint(OutFile, "\t%g")     
  OutFile.close

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