drift-diffusion simulation of channels & synapses carl ...gardner/siam16.pdf · arizona state...
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![Page 1: Drift-Diffusion Simulation of Channels & Synapses Carl ...gardner/SIAM16.pdf · Arizona State University. ... Simulate time-dependent equations to steady state ... homogeneous Neumann](https://reader031.vdocuments.us/reader031/viewer/2022022017/5b846d467f8b9ad34a8c3762/html5/thumbnails/1.jpg)
Drift-Diffusion Simulation of Channels & Synapses
Carl Gardner, Jeremiah Jones, Steve Baer, & Sharon Crook
School of Mathematical & Statistical Sciences
Arizona State University
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Drift-Diffusion (PNP) Model
∂ni
∂t+∇· fi = 0, i = Ca2+, Na+, K+, Cl−
fi = ziµiniE − Di∇ni, zi =qi
qe
, ji = qifi, j =∑
i
ji
parabolic/elliptic system of PDEs:
∂ni
∂t+∇· (ziµiniE) = Di∇2ni, i = Ca2+, Na+, K+, Cl−
∇· (ǫ∇φ) = −∑
i
qini, E = −∇φ
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Numerical Methods
Simulate time-dependent equations to steady state ∼ 100,000
timesteps for triad synapse
Given initial data, for each ∆t:
(i) Compute φ from Poisson’s equation with Dirichlet/Neumann BCs
using “chaotic relaxation” Chebyshev SOR
(ii) Compute ni from drift-diffusion equations with Dirichlet/
Neumann BCs using TRBDF2
(iii) Membrane sweep: Update σ±
i from dσ±
i /dt equations using
TRBDF2 & transcribe to n±i ; update φ± with two jump conditions
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TRBDF2 Method
TR
BDF2
n+1n
Timelevel n + γ = n + (2 −√
2). For du/dt = f (u):
TR step
un+γ − γ∆tn
2f n+γ = un + γ
∆tn
2f n
BDF2 step
un+1 − 1 − γ
2 − γ∆tnf n+1 =
1
γ(2 − γ)un+γ − (1 − γ)2
γ(2 − γ)un
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Modeling Ionic Flow in Biological Channels
Carl Gardner & Jeremiah Jones
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region l Q ǫ µ D z interval
interior bath 5 0 80 60 1.5 [−5, 0)−4e group 0.2 −4e 80 16 0.4 [0, 0.2]nonpolar 1.1 0 30 16 0.4 (0.2, 1.3)central cavity 1 −e/2 30 16 0.4 [1.3, 2.3]filter 1.2 −3e/2 30 16 0.4 (2.3, 3.5]exterior bath 5 0 80 60 1.5 (3.5, 8.5]
l & z in nm, background permanent Q on the protein, dielectric
constants ǫ, mobility coefficients µ in 10−5 cm2/(V s), & diffusion
coefficients D in 10−5 cm2/s
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z
r
l cl b l b
membranebath bath
r c
r b
channel
interior exterior
no-flux BC
ambient BC ambient BC
far-field
BC
far-field
BC
ambient BC ambient BC
membrane
interior
no-flux BC
ni = Nbi, φ = {V, 0} (bath far-field BC)
ni = Nbi,∂φ
∂r= 0 (ambient bath BC)
n̂ · ∇ni = 0, n̂ · ∇φ = 0 (no-flux BC)
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−4 −2 0 2 4 6 8−3.5
−3
−2.5
−2
−1.5
−1
−0.5
0
0.5
1
1.5
z
Log(
Den
sity
)
Simulation of log10
(
{nK , nCl}/(
1021 cm−3))
for V = 100 millivolts
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Simulation of log10
(
nK/(
1021 cm−3))
for V = 100 millivolts
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Simulation of log10
(
nCl/(
1021 cm−3))
for V = 100 millivolts
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Simulation of electrostatic potential in volts for V = 0.1 volts
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1008060402000
5
10
15
20
25
Voltage
Cur
rent
Current in picoamps vs. applied voltage in millivolts
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0 10 20 30 40 50 60 70 80 90 1000
20
40
Time
Cur
rent
0 10 20 30 40 50 60 70 80 90 1000
50
100
Vol
tage
Simulation of current in pA vs. time in ns for an applied voltage ramp
in millivolts
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0 10 20 30 40 50 60 70 80 90 100−40
−20
0
20
40
Cur
rent
Time0 10 20 30 40 50 60 70 80 90 100
−40
−20
0
20
40
0 10 20 30 40 50 60 70 80 90 100−100
−50
0
50
100
Vol
tage
Simulation of current in pA vs. time in ns for a sinusoidal applied
voltage in millivolts with ω = 3 GHz
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Drift-Diffusion Simulation of the Ephaptic Effect
in the Triad Synapse of the Retina
Carl Gardner, Jeremiah Jones, Steve Baer, & Sharon Crook
http://webvision.med.utah.edu/
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Schematic of cone pedicle showing four triad synapses
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Schematic (Kamermans & Fahrenfort) of horizontal cell dendrite
contacting cone pedicle: simulate 600 nm × 900 nm region
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Ephaptic Effect
1. Experiments show illumination of cone causes hyperpolarization
of horizontal cells & increased levels of intracellular cone Ca
(Ca2+ current flows into cone)
2. Ephaptic hypothesis: specialized geometry of synapse can force
currents through high-resistance bottlenecks causing potential
drop in extracellular cleft
3. Cone membrane senses this as depolarization, which increases
activation of voltage-sensitive Ca channels
4. Implies Ca2+ current is directly modulated by electric potential
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A Model of the Membrane
(similar to Mori-Jerome-Peskin)
minside
outside
+Σ
-Σ
Φ
Φ+
Φ-
Φ
ni
ni
Σi+
Σi-
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+−
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Jump conditions for Poisson’s equation
[φ] ≡ φ+ − φ− = V =σ
Cm
[n̂ · ∇φ] = 0
BCs for drift-diffusion equation (Mori-Jerome-Peskin), but we use
σ±
i = qil±
D
(
n±i − n±bi
)
∂σ±
i
∂t= qil
±
D
∂n±i∂t
= −l±D∇· j±i ∓ jmi
σ ≡∑
i
σ+
i = −∑
i
σ−
i
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HC
CP
BC
UCP
UBC
UHC
Uref
Along axis of symmetry, homogeneous Neumann BCs for ni & φ;
along other outer boundaries, Dirichlet (bath) BCs for ni &
homogeneous Neumann or Dirichlet (colors) BCs for φ: Uref = −40
mV, UHC = −60 (on) or −40 (off) mV, UBC = −80, −60, or −40 mV,
UCP = −80 to +10 mV
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Known Biological Parameters
Parameter Value Description
nb,Ca 10−4, 2 mM intra/extracellular bath density of Ca2+
nb,Na 10, 140 mM intra/extracellular bath density of Na+
nb,K 150, 2.5 mM intra/extracellular bath density of K+
nb,Cl 160, 146.5 mM intra/extracellular bath density of Cl−
ǫ 80 dielectric coefficient of water
Ns 20 number of spine heads per cone pedicle
Am 0.1 µm2 spine head area
Cm 1 µF/cm2 membrane capacitance per area
VCa 50 mV reversal potential for Ca2+
VNa 50 mV reversal potential for Na+
VK −60 mV reversal potential for K+
Ghemi 5.5 nS hemichannel conductance
mM = 6 × 1017 ions/cm3
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Known Biological Parameters
Parameter Value Description
DCa 0.8 nm2/ns diffusivity of Ca2+
DNa 1.3 nm2/ns diffusivity of Na+
DK 2 nm2/ns diffusivity of K+
DCl 2 nm2/ns diffusivity of Cl−
µCa 32 nm2/(V ns) mobility of Ca2+
µNa 52 nm2/(V ns) mobility of Na+
µK 80 nm2/(V ns) mobility of K+
µCl 80 nm2/(V ns) mobility of Cl−
Einstein relation: Di = µikT/qe
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Transmembrane Currents
jhemi =∑
cations
gi (VHC − Vi) = ghemiVHC
jm,Ca =gCa (VCP − ECa)
1 + exp{(θ − VCP) /λ}Parameter Value Description
ECa 50 mV cone reversal potential for Ca2+
GCa 2.2 nS Ca conductance
θ 5 mV kinetic parameter (independent of bg)
λ 3 mV kinetic parameter
gi = Gi/(NsAm); ICa = Ns
∫
Amjm,Ca da flows into cone
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−80 −60 −40 −20 0−80
−60
−40
−20
0
Holding Potential (mV)
Cal
cium
Cur
rent
(pA
)Neutral Bipolar Cell
HC/BC = −40/−60HC/BC = −60/−60
−80 −60 −40 −20 0−80
−60
−40
−20
0
Holding Potential (mV)
Cal
cium
Cur
rent
(pA
)
Depolarized Bipolar Cell
HC/BC = −40/−60HC/BC = −60/−40
−80 −60 −40 −20 0−80
−60
−40
−20
0
Holding Potential (mV)
Cal
cium
Cur
rent
(pA
)
Hyperpolarized Bipolar Cell
HC/BC = −40/−60HC/BC = −60/−80
−80 −60 −40 −20 0−50
0
50
100
Holding Potential (mV)C
urre
nt S
hift
(pA
)
Shift Curves
NeutralDepolarizedHyperpolarized
3-parameter fit to background off (blue) curve; then background on
(red) curve is a prediction of the model
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2D Complex Geometry of the Synapse
1. Model effects of complex geometry
2. Specify holding potential UCP as in voltage clamp experiment
3. Apply 2D TRBDF2 drift-diffusion code (with Chebyshev SOR
for Poisson equation) inside cells as well as outside, along with
membrane boundary conditions
4. Computed potential shows simple compartment model is not
adequate for triad synapse
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Numerical Methods
TRBDF2 for drift-diffusion equations (about 30% of computation
time), “chaotic relaxation” Chebyshev SOR for Poisson equation
(about 70%), membrane BCs (about 1%) on 600 × 900 fine grid
OpenMP gives speedup ∼ Ncores/2
∆t ∼ 1 ps initially → 50 ps, charge layer relaxation ∼ 1 ns
Steady state ∼ 1 µs, GABA diffusion ∼ 1 ms
Solution computed on 600 × 900 fine grid on 96 cores ∼ 1 hr
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UCP = 0 mV, UHC = −40,−60 mV, UBC = −60 mV
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UCP = −20 mV, UHC = −40,−60 mV, UBC = −60 mV
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UCP = −40 mV, UHC = −40,−60 mV, UBC = −60 mV
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UCP = −60 mV, UHC = −40,−60 mV, UBC = −60 mV
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UCP = −20 mV, UBC = −60 mV, UBC = −60 mV
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Experimental IV curves (Kamermans & Fahrenfort)
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Experimental IV curves (Kamermans et al.)
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−80 −60 −40 −20 0−80
−60
−40
−20
0
Holding Potential (mV)
Cal
cium
Cur
rent
(pA
)Neutral Bipolar Cell
HC/BC = −40/−60HC/BC = −60/−60
−80 −60 −40 −20 0−80
−60
−40
−20
0
Holding Potential (mV)
Cal
cium
Cur
rent
(pA
)
Depolarized Bipolar Cell
HC/BC = −40/−60HC/BC = −60/−40
−80 −60 −40 −20 0−80
−60
−40
−20
0
Holding Potential (mV)
Cal
cium
Cur
rent
(pA
)
Hyperpolarized Bipolar Cell
HC/BC = −40/−60HC/BC = −60/−80
−80 −60 −40 −20 0−50
0
50
100
Holding Potential (mV)C
urre
nt S
hift
(pA
)
Shift Curves
NeutralDepolarizedHyperpolarized
3-parameter fit to background off (blue) curve; then background on
(red) curve is a prediction of the model
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Future Work
1. Model nonperiodic arrays of synapses in order to realistically
model entire cone pedicle
2. Multiscale modeling: integrate out shortest time scales in
drift-diffusion model to obtain intermediate model, so we can
treat time-dependent illuminations of retina