Active dendrites shape signaling microdomains in hippocampal neurons (Basak & Narayanan 2018)

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Accession:244848
The spatiotemporal spread of biochemical signals in neurons and other cells regulate signaling specificity, tuning of signal propagation, along with specificity and clustering of adaptive plasticity. Theoretical and experimental studies have demonstrated a critical role for cellular morphology and the topology of signaling networks in regulating this spread. In this study, we add a significantly complex dimension to this narrative by demonstrating that voltage-gated ion channels (A-type Potassium channels and T-type Calcium channels) on the plasma membrane could actively amplify or suppress the strength and spread of downstream signaling components. We employed a multiscale, multicompartmental, morphologically realistic, conductance-based model that accounted for the biophysics of electrical signaling and the biochemistry of calcium handling and downstream enzymatic signaling in a hippocampal pyramidal neuron. We chose the calcium – calmodulin – calcium/calmodulin-dependent protein kinase II (CaMKII) – protein phosphatase 1 (PP1) signaling pathway owing to its critical importance to several forms of neuronal plasticity, and employed physiologically relevant theta-burst stimulation (TBS) or theta-burst pairing (TBP) protocol to initiate a calcium microdomain through NMDAR activation at a synapse.
Reference:
1 . Basak R, Narayanan R (2018) Active dendrites regulate the spatiotemporal spread of signaling microdomains. PLoS Comput Biol 14:e1006485 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Dendrite; Synapse; Channel/Receptor; Neuron or other electrically excitable cell;
Brain Region(s)/Organism: Hippocampus;
Cell Type(s): Hippocampus CA1 pyramidal cell;
Channel(s): Ca pump; I A; I_SERCA; I Calcium; I_K,Na; I h; I Potassium;
Gap Junctions:
Receptor(s): AMPA; NMDA;
Gene(s):
Transmitter(s):
Simulation Environment: NEURON;
Model Concept(s): Active Dendrites; Detailed Neuronal Models; Calcium dynamics; Reaction-diffusion; Signaling pathways; Synaptic Plasticity;
Implementer(s): Basak, Reshma [reshmab at iisc.ac.in]; Narayanan, Rishikesh [rishi at iisc.ac.in];
Search NeuronDB for information about:  Hippocampus CA1 pyramidal cell; AMPA; NMDA; I A; I h; I Calcium; I Potassium; I_SERCA; I_K,Na; Ca pump;
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Basak_Narayayanan_2018
Spine1000_sample
readme.txt
apamp.mod
caminmax.mod
car.mod
cat.mod
ghkampa.mod
ghknmda.mod
h.mod
kadist.mod *
kaprox.mod
kdrca1.mod *
modcamechs.mod
na3.mod
nax.mod
vmax.mod
distance.hoc
distance_SD.hoc
Fig_13.hoc
mosinit.hoc
n123.hoc *
ObliquePath.hoc *
oblique-paths.hoc *
Sample_output_Calcium.txt
                            
COMMENT
Two state kinetic scheme synapse described by rise time taur,
and decay time constant taud. The normalized peak condunductance is 1.
Decay time MUST be greater than rise time.

The solution of A->G->bath with rate constants 1/taur and 1/taud is
 A = a*exp(-t/taur) and
 G = a*taud/(taud-taur)*(-exp(-t/taur) + exp(-t/taud))
	where taur < taud

If taud-taur -> 0 then we have a alphasynapse.
and if taur -> 0 then we have just single exponential decay.

The factor is evaluated in the
initial block such that an event of weight 1 generates a
peak conductance of 1.

Because the solution is a sum of exponentials, the
coupled equations can be solved as a pair of independent equations
by the more efficient cnexp method.

ENDCOMMENT

NEURON {
	POINT_PROCESS ghknmda
	USEION na WRITE ina
	USEION k WRITE ik
	USEION ca READ cai, cao WRITE ica
	
	RANGE taur, taud
	RANGE inmda

	RANGE P, mg, Pmax :AreaFactor
	GLOBAL  mgb
}

UNITS {
	(nA) = (nanoamp)
	(mV) = (millivolt)
	(uS) = (microsiemens)
	(molar) = (1/liter)
	(mM) = (millimolar)
	FARADAY = (faraday) (coulomb)
	R = (k-mole) (joule/degC)
  	(um)    = (micron)
  	PI      = (pi)       (1)

}

PARAMETER {
	taur=5 (ms) <1e-9,1e9>
	taud = 50 (ms) <1e-9,1e9>
	cai = 50e-6(mM)	: 100nM
	cao = 2		(mM)
	nai = 18	(mM)	: Set for a reversal pot of +55mV
	nao = 140	(mM)
	ki = 140	(mM)	: Set for a reversal pot of -90mV
	ko = 5		(mM)
	celsius		(degC)
	mg = 2		(mM)
	Pmax=1e-6   (cm/s)	: According to Canavier, PNMDA's default value is
						: 1e-6 for 10uM, 1.4e-6 cm/s for 30uM of NMDA
	:AreaFactor =250 (cm2) : Computed from PI*Diam*1e2
}

ASSIGNED {
	ina     (mA/cm2)
	ik      (mA/cm2)
	ica     (mA/cm2)
	v (mV)
	P (cm/s)
	factor
	mgb	(1)
	inmda	(mA/cm2)

	diam (um)
}

STATE {
	A (cm/s)
	B (cm/s)
}

INITIAL {
	LOCAL tp
	if (taur/taud > .9999) {
		taur = .9999*taud
	}
	A = 0
	B = 0
	tp = (taur*taud)/(taud - taur) * log(taud/taur)
	factor = -exp(-tp/taur) + exp(-tp/taud)
	factor = 1/factor
}

BREAKPOINT {
	SOLVE state METHOD cnexp
	P=B-A
	mgb = mgblock(v)

: Area is for unit conversion from nA to mA/cm2 which is what ica, ina and ik use.
 
	ina = P*mgb*ghk(v, nai, nao,1)     :/AreaFactor	
	ica = P*10.6*mgb*ghk(v, cai, cao,2)  :/AreaFactor
	ik = P*mgb*ghk(v, ki, ko,1)      :/AreaFactor
	inmda = ica + ik + ina
}

DERIVATIVE state {
	A' = -A/taur
	B' = -B/taud
}

FUNCTION ghk(v(mV), ci(mM), co(mM),z) (0.001 coul/cm3) {
	LOCAL arg, eci, eco
	arg = (0.001)*z*FARADAY*v/(R*(celsius+273.15))
	eco = co*efun(arg)
	eci = ci*efun(-arg)
	ghk = (0.001)*z*FARADAY*(eci - eco)
}

FUNCTION efun(z) {
	if (fabs(z) < 1e-4) {
		efun = 1 - z/2
	}else{
		efun = z/(exp(z) - 1)
	}
}

FUNCTION mgblock(v(mV)) (1){
	TABLE 
	DEPEND mg
	FROM -140 TO 80 WITH 1000 

	: from Jahr & Stevens, JNS, 1990

	mgblock = 1 / (1 + exp(0.062 (/mV) * -v) * (mg / 3.57 (mM)))
}

NET_RECEIVE(weight (uS)) { 	: No use to weight, can be used instead of Pmax,
							: if you want NetCon access to the synaptic
							: conductance.
	state_discontinuity(A, A + Pmax*factor)
	state_discontinuity(B, B + Pmax*factor)
}

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