TITLE Triple-exp model of NMDAR has (HH-type gating) (temp. sensitivity) (voltage-dependent time constants) (desensitization)
COMMENT
This is a Triple-exponential model of an NMDAR
that has a slow voltage-dependent gating component in its conductance
time constants are voltage-dependent and temperature sensitive
Mg++ voltage dependency from Spruston95 -> Woodhull, 1973
Desensitization is introduced in this model. Actually, this model has 4 differential equations
becasue desensitization is solved analitically. It can be reduced to 3 by solving its A state analitically.
For more info read the original paper.
Keivan Moradi 2012
ENDCOMMENT
NEURON {
POINT_PROCESS Exp5NMDA
NONSPECIFIC_CURRENT i
RANGE tau1, tau2_0, a2, b2, wtau2, tau3_0, a3, b3, tauV, e, i, gVI, gVDst, gVDv0, Mg, K0, delta, tp, wf, tau_D1, d1
GLOBAL inf, tau2, tau3
THREADSAFE
}
UNITS {
(nA) = (nanoamp)
(mV) = (millivolt)
(uS) = (microsiemens)
(mM) = (milli/liter)
(S) = (siemens)
(pS) = (picosiemens)
(um) = (micron)
(J) = (joules)
}
PARAMETER {
: Parameters Control Neurotransmitter and Voltage-dependent gating of NMDAR
tau1 = 1.69 (ms) <1e-9,1e9> : Spruston95 CA1 dend [Mg=0 v=-80 celcius=18] be careful: Mg can change these values
: parameters control exponential rise to a maximum of tau2
tau2_0 = 3.97 (ms)
a2 = 0.70 (ms)
b2 = 0.0243 (1/mV)
wtau2= 0.65 <1e-9,1> : Hestrin90
: parameters control exponential rise to a maximum of tau3
tau3_0 = 41.62 (ms)
a3 = 34.69 (ms)
b3 = 0.01 (1/mV)
: Hestrin90 CA1 soma [Mg=1 v=-40 celcius=30-32] the decay of the NMDA component of the EPSC recorded at temperatures above 30 degC
: the fast phase of decay, which accounted for 65%-+12% of the decay, had a time constant of 23.5-+3.8 ms,
: whereas the slow component had a time constant of 123-+83 ms.
: wtau2= 0.78 Spruston95 CA1 dend [Mg=0 v=-80 celcius=18] percentage of contribution of tau2 in deactivation of NMDAR
Q10_tau1 = 2.2 : Hestrin90
Q10_tau2 = 3.68 : Hestrin90 -> 3.5-+0.9, Korinek10 -> NR1/2B -> 3.68
Q10_tau3 = 2.65 : Korinek10
T0_tau = 35 (degC) : reference temperature
: Hestrin90 CA1 soma [Mg=1 v=-40 celcius=31.5->25] The average Q10 for the rising phase was 2.2-+0.5,
: and that for the major fast decaying phase was 3.5-+0.9
tp = 30 (ms) : time of the peack -> when C + B - A reaches the maximum value or simply when NMDA has the peack current
: tp should be recalculated when tau1 or tau2 or tau3 changes
: Parameters control desensitization of the channel
: these values are from Fig.3 in Varela et al. 1997
: the (1) is needed for the range limits to be effective
d1 = 0.2 (1) < 0, 1 > : fast depression
tau_D1 = 2500 (ms) < 1e-9, 1e9 >
: Parameters Control voltage-dependent gating of NMDAR
tauV = 7 (ms) <1e-9,1e9> : Kim11
: at 26 degC & [Mg]o = 1 mM,
: [Mg]o = 0 reduces value of this parameter
: Because TauV at room temperature (20) & [Mg]o = 1 mM is 9.12 Clarke08 & Kim11
: and because Q10 at 26 degC is 1.52
: then tauV at 26 degC should be 7
gVDst = 0.007 (1/mV) : steepness of the gVD-V graph from Clarke08 -> 2 units / 285 mv
gVDv0 = -100 (mV) : Membrane potential at which there is no voltage dependent current, from Clarke08 -> -90 or -100
gVI = 1 (uS) : Maximum Conductance of Voltage Independent component, This value is used to calculate gVD
Q10 = 1.52 : Kim11
T0 = 26 (degC) : reference temperature
celsius (degC) : actual temperature for simulation, defined in Neuron
: Parameters Control Mg block of NMDAR
Mg = 1 (mM) : external magnesium concentration from Spruston95
K0 = 4.1 (mM) : IC50 at 0 mV from Spruston95
delta = 0.8 (1) : the electrical distance of the Mg2+ binding site from the outside of the membrane from Spruston95
: The Parameter Controls Ohm haw in NMDAR
e = -0.7 (mV) : in CA1-CA3 region = -0.7 from Spruston95
}
CONSTANT {
T = 273.16 (degC)
F = 9.648e4 (coul) : Faraday's constant (coulombs/mol)
R = 8.315 (J/degC): universal gas constant (joules/mol/K)
z = 2 (1) : valency of Mg2+
}
ASSIGNED {
v (mV)
dt (ms)
i (nA)
g (uS)
factor
wf
q10_tau2
q10_tau3
inf (uS)
tau (ms)
tau2 (ms)
tau3 (ms)
wtau3
}
STATE {
A : Gating in response to release of Glutamate
B : Gating in response to release of Glutamate
C : Gating in response to release of Glutamate
gVD (uS): Voltage dependent gating
}
INITIAL {
Mgblock(v)
: temperature-sensitivity of the of NMDARs
tau1 = tau1 * Q10_tau1^((T0_tau - celsius)/10(degC))
q10_tau2 = Q10_tau2^((T0_tau - celsius)/10(degC))
q10_tau3 = Q10_tau3^((T0_tau - celsius)/10(degC))
: temperature-sensitivity of the slow unblock of NMDARs
tau = tauV * Q10^((T0 - celsius)/10(degC))
rates(v)
wtau3 = 1 - wtau2
: if tau3 >> tau2 and wtau3 << wtau2 -> Maximum conductance is determined by tau1 and tau2
: tp = tau1*tau2*log(tau2/(wtau2*tau1))/(tau2 - tau1)
factor = -exp(-tp/tau1) + wtau2*exp(-tp/tau2) + wtau3*exp(-tp/tau3)
factor = 1/factor
A = 0
B = 0
C = 0
gVD = 0
wf = 1
}
BREAKPOINT {
SOLVE state METHOD runge : derivimplicit :
: we found acceptable results with "runge" integration method
: However, M. Hines encouraged us to use "derivimplicit" method instead - which is slightly slower than runge -
: to avoid probable unstability problems
i = (wtau3*C + wtau2*B - A)*(gVI + gVD)*Mgblock(v)*(v - e)
}
DERIVATIVE state {
rates(v)
A' = -A/tau1
B' = -B/tau2
C' = -C/tau3
: Voltage Dapaendent Gating of NMDA needs prior binding to Glutamate Kim11
gVD' = ((wtau3*C + wtau2*B)/wf)*(inf-gVD)/tau
: gVD' = (inf-gVD)/tau
}
NET_RECEIVE(weight, D1, tsyn (ms)) {
INITIAL {
: these are in NET_RECEIVE to be per-stream
: this header will appear once per stream
D1 = 1
tsyn = t
}
D1 = 1 - (1-D1)*exp(-(t - tsyn)/tau_D1)
tsyn = t
wf = weight*factor*D1
A = A + wf
B = B + wf
C = C + wf
D1 = D1 * d1
}
FUNCTION Mgblock(v(mV)) {
: from Spruston95
Mgblock = 1 / (1 + (Mg/K0)*exp((0.001)*(-z)*delta*F*v/R/(T+celsius)))
}
PROCEDURE rates(v (mV)) {
inf = (v - gVDv0) * gVDst * gVI
tau2 = (tau2_0 + a2*(1-exp(-b2*v)))*q10_tau2
tau3 = (tau3_0 + a3*(1-exp(-b3*v)))*q10_tau3
if (tau1/tau2 > .9999) {
tau1 = .9999*tau2
}
if (tau2/tau3 > .9999) {
tau2 = .9999*tau3
}
}