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0-or-1 LTD is like Shishi Odoshi
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Masao Ito,
Nat Rev Neurosci
3, 896-902 (2002)
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Doi T, Kuroda S, Michikawa T, Kawato M: IP3-dependent Ca2+ threshold dynamics detect spike-timing
in cerebellar Purkinje Cells. Journal of Neuroscience, 25, 950-961 (2005).
Ca2+ Wang et al., Nat Neurosci
3, 1266-1273 (2000)
Ca2+
(1) A+B
kf
kb
AB
d[AB]/dt = + kf[A][B] - kb[AB]
d[A]/dt = kf [A][B] + kb[AB]
[A] + [AB] = [A]total = const.
Kd=kb/kf =1/(kf +kb)
PF Ca2+IP3
CF Ca2+
586;1+
PFCF
Ca2+
Unknown/Total
Ca2+ Kd
Michaelis Km
Vmax
[A]
31 / 34
Wang et al., (2000) Nat Neurosci
3 / 29
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3 / 21
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(i) CFLTD
(ii) PFLTD
(iii) PFCF
LTD
(iv)Ca2+LTD
(v) IP3LTD
(vi)PFLTD
LTD
NO
membrane
CRF
Glutamate
CRHR
Ica
AMPA R
Na/Ca
membrane
Raf
PKC
G substrate
MEK
DAG
AA
CRHR
CRHR
GC
PKC
MEK
Positive
feedback
loop
PLC
DAG
AA
PLA2
MAP kinase
Glutamate
Glutamate
CRF
NO
Ica
Ica
AMPA R
Na/Ca
membrane
mGlu
mGlu R
R
IP3
Raf
PKC
Positive
feedback
loop
MEK
MAP kinase
DAG
Ica
Raf
Positive
feedback
loop
AA
PKC
MEK
MAP kinase
DAG
DAG
AA
PLA2
PLC
[Ca22++]
PKG
PP2A
mGlu R
IP3
PLA2
Gq
G substrate
Na/Ca
AMPA R
R
AMPA
Lyn
cGMP
PLC
[Ca22++]]
CRHR
GC
Gq
G substrate
mGlu R
[C
a2+]
Raf
PP2A
PP2A
cGMP
Gq
Lyn
PKG
Na/Ca
G substrate
IP3
PKG
PLA2
AMPA R
Lyn
CRF
CRF
NO
Ica
cGMP
CRHR
PLC
[C
a2+]
Positive
feedback
loop
MAP kinase
Glutamate
GC
IP3
PP2A
mGlu R
Gq
Lyn
cGMP
membrane
CRF
NO
GC
PKG
P P
0.5
100
0.4
80
Non-Phosphorylated 60
AMPA Receptors
0.3
40
0.2
Phosphorylated AMPA Receptors
0.1
0
0
10
AMPA R
Lyn
Time (min)
Update on experimental tests of Kuroda
et al. positive feedback model
George AugustineDuke
•Ca2+ photo-uncaging control
•Ca2+ Confocal microscope measurement
Ca-uncaging, Ca-imaging, Whole
Cell Clamp, and PF Stimulation
Ca2+
Raf
PKC
DAG
CRF
Positive
feedback
loop
MEK
20
0
20 30 40 50 60 70 80 90 100
AMPA
R -RP
AMPA
NO
PP2A
MAP kinase
AA
PLA2
AMPA phosphorylation (μM)
MAPK
LTD
EPSP (%)
AMPA receptor (μM)
LTD
Simulation data
0.3
Deleted pathways
control
0.2
0.1
0
0
10
Block MAP kinase
20 30 40
50 60 70 80
Time (min)
Ca2+1$2%1#
Ca2+
9<7
Neuron, 54, 1-14, June 7, 2007
• George Augustine
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02.
Ca2+
Ca2+ threshold for
LTD induction
90 100
Ca2+
requirements for LTD
Leaky Integrate
and Depress Model
dx
= x + a[Ca 2+ ]i (t)
dt
(1)
[sec]: the time constant of the leaky integrator.
a[%/ μ M]: the gain from [Ca 2+ ]i to %.
(2)
[Ca 2+ ]i (t) = kt
By substituting Eq. (2) to Eq. (1), we obtain;
dx
= x + akt
dt
(3)
t
x(t) = ak exp + ak(t )
Experimental
confirmation
that dynamic
Ca2+ threshold
depends on
MAPK positive
feedback loop
(4)
Positive feedback loop between
PKC and MAPK
MAPK inhibitor
MAPK
Ca2+
PKC
PKC inhibitor
LTD
Bhalla US and Iyengar R; Science (1999)
Kuroda S et al.; Journal of Neuroscience (2001)
Doi T et al.; Journal of Neuroscience (2005)
Tanaka K et al.; Neuron (2007)
Tanaka K and Augustine GJ; Neuron (2008)
Ogasawara H and Kawato M; Science Signaling (2009)
Computational Schema of LTD
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