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

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"... 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..."
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
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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;
Gap Junctions:
Receptor(s): GabaA; AMPA; NMDA;
Transmitter(s): Gaba; Glutamate;
Simulation Environment: NEURON;
Model Concept(s): Short-term Synaptic Plasticity; Synaptic Plasticity; Chloride regulation;
Implementer(s): Jedlicka, Peter [jedlicka at]; Kilb, Werner [wkilb at];
Search NeuronDB for information about:  Hippocampus CA3 pyramidal GLU cell; GabaA; AMPA; NMDA; Gaba; Glutamate;
_For Zip -Neuron-Models_AMPA-GABA
cldif_CA3_NKCC1_HCO3.mod *
gabaA_Cl_HCO3.mod *
vecevent.mod *
Cell1_Cl_HCO3_Pas_fine.hoc * *

Chloride accumulation and diffusion with decay (time constant tau) to resting level cli0.
The decay approximates a reversible chloride pump with first order kinetics.
To eliminate the chloride pump, just use this hoc statement
To make the time constant effectively "infinite".
tau and the resting level are both RANGE variables

Diffusion model is modified from Ca diffusion model in Hines & Carnevale:
Expanding NEURON with NMODL, Neural Computation 12: 839-851, 2000 (Example 8)


	USEION cl READ icl WRITE cli VALENCE -1 : Ion cl, use cl current to calculate cl internal concentration
	USEION hco3 READ ihco3 WRITE hco3i VALENCE -1: Ion HCO3, use HCO3 internal concentration to calculate the external concentration
	GLOBAL vrat		:vrat must be GLOBAL, so it does not change with position. vrat = volumes of concentric shells
	RANGE tau, cli0, clo0, hco3i0, hco3o0, egaba, delta_egaba, init_egaba, ehco3_help, ecl_help : all of these change with position

DEFINE Nannuli 4

	(molar) = (1/liter)
	(mM) = (millimolar)
	(um) = (micron)
	(mA) = (milliamp)
	(mV)    = (millivolt)
	FARADAY = (faraday) (10000 coulomb)
	PI = (pi) (1)
	F = (faraday) (coulombs)
	R = (k-mole)  (joule/degC)

	DCl = 2 (um2/ms) : Kuner & Augustine, Neuron 27: 447 : diffusion coefficient of cl
        DHCO3 = 1.18 (um2/ms) : Hashitani & Kigoshi,  Bulletin of the Chemical Society of Japan, 38:1395-1396
	tau_NKCC1 = 174000 (ms)   : 174 s From Kolbaev, Lombardi kilb (in Prep) - kinetics after Cl decline
	tau_passive = 321000 (ms) : 321 s From Kolbaev, Lombardi Kilb (in prep) - kinetics after bumetanid washin
        tau_hco3 = 1000 (ms) : tau for Bicarbonate, just an arbitrary value
	cli0 = 50 (mM) : basal Cl internal concentration
	cli_Start = 10 (mM) :Cl- concentration at start
	clo0 = 133.5 (mM) : basal Cl external concentration
	hco3i0 = 16	(mM) : basal HCO3 internal concentration
	hco3o0 = 26	(mM) : basal HCO3 external concentration
	hco3i_Start = 16 (mM) : Cl- concentration at start
	celsius = 31    (degC)


	diam 	(um)
	icl 	(mA/cm2) : Cl current
        ihco3 	(mA/cm2) : HCO3- current current
	cli 	(mM) : Cl internal concentration
	hco3i	(mM) : HCO3 internal concentration
	hco3o	(mM) : HCO3 external concentration
	vrat[Nannuli]	: numeric value of vrat[i] equals the volume
			: of annulus i of a 1um diameter cylinder
			: multiply by diam^2 to get volume per um length
	ehco3_help 	(mV)
	ecl_help	(mV)
	ActPump   :Binary value that defines if active inward pumping of passive outward diffusion

	: cl[0] is equivalent to cli
	: cl[] are very small, so specify absolute tolerance
	cl[Nannuli]	(mM) <1e-10>
        hco3[Nannuli]	(mM) <1e-10>

		SOLVE state METHOD sparse
		ecl_help = log(cli/clo0)*(1000)*(celsius + 273.15)*R/F
                ehco3_help = log(hco3i/hco3o0)*(1000)*(celsius + 273.15)*R/F

LOCAL factors_done

	if (factors_done == 0) {  	: flag becomes 1 in the first segment
		factors_done = 1	: all subsequent segments will have
		factors()		: vrat = 0 unless vrat is GLOBAL. We make sure that vrat is applied to the shell volumes
	cli = cli_Start
	hco3i = hco3i0
	hco3o = hco3o0
	FROM i=0 TO Nannuli-1 { : So that at the begining the Cl [] is the same in all shells ( steady state)
		cl[i] = cli
        FROM i=0 TO Nannuli-1 { : So that at the begining the HCO3 [] is the same in all shells ( steady state)
		hco3[i] = hco3i
	ehco3_help = log(hco3i/hco3o)*(1000)*(celsius + 273.15)*R/F : Nerst eq for HCO3 at time 0
	ecl_help = log(cli/clo0)*(1000)*(celsius + 273.15)*R/F

LOCAL frat[Nannuli]	: scales the rate constants for model geometry

PROCEDURE factors() {
	LOCAL r, dr2
	r = 1/2			: starts at edge (half diam), diam = 1, length = 1
	dr2 = r/(Nannuli-1)/2	: full thickness of outermost annulus,
				: half thickness of all other annuli
	vrat[0] = 0
	frat[0] = 2*r		: = diam
	FROM i=0 TO Nannuli-2 {
		vrat[i] = vrat[i] + PI*(r-dr2/2)*2*dr2	: interior half
		r = r - dr2
		frat[i+1] = 2*PI*r/(2*dr2)	: outer radius of annulus Ai+1/delta_r=2PI*r*1/delta_r
						: div by distance between centers
		r = r - dr2
		vrat[i+1] = PI*(r+dr2/2)*2*dr2	: outer half of annulus

KINETIC state {
    if (cli0 >= cl[0]) { : Under this condition the NKCC1 mediates active Cl- uptake ( positive inward flux)
		  ActPump = 1
		else {     : Under this condition NKCC1 should be not functional ( negative inward flux)
		  ActPump = 0

  	COMPARTMENT i, diam*diam*vrat[i] {cl}
		LONGITUDINAL_DIFFUSION i, DCl*diam*diam*vrat[i] {cl}
				~ cl[0] << ((icl*PI*diam/FARADAY) + ActPump*(diam*diam*vrat[0]*(cli0 - cl[0])/tau_NKCC1) + (diam*diam*vrat[0]*(cli0 - cl[0])/tau_passive)) : icl is Cl- influx
	 	FROM i=0 TO Nannuli-2 {
		~ cl[i] <-> cl[i+1]	(DCl*frat[i+1], DCl*frat[i+1])
	        cli = cl[0]

        COMPARTMENT i, diam*diam*vrat[i] {hco3}
		LONGITUDINAL_DIFFUSION i, DHCO3*diam*diam*vrat[i] {hco3}
				~ hco3[0] << ((ihco3*PI*diam/FARADAY)  + (diam*diam*vrat[0]*(hco3i0 - hco3[0])/tau_hco3)) : ihco3 is HCO3- influx
	 	FROM i=0 TO Nannuli-2 {
		~ hco3[i] <-> hco3[i+1]	(DHCO3*frat[i+1], DHCO3*frat[i+1])
	        hco3i = hco3[0]