Neural Circuit of Cerebellar Cortex

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Neural Circuit of Cerebellar Cortex
2
???????????????
CF
PF
Glu
NO
CRF
AMPA-R
VGCC
mGluR
CRHR
PLC
GC
Gq
Lyn
cGMP
Ca2
PKC
PKG
DAG
IP3
Raf
G-substrate
Positive Feedback Loop
IP3R
AA
MEK
Ca2 Store
PP2A
PLA2
MAPK
3
?????????
???? PF

1. ??????????????
2. PF??????CF?????
3. PF????????????CF?????????????????????(?????LTD)

????? ??
???? CF
4
??LTD???????
????(PF)? ????(CF)? ?????????
????
????
?????Ca2?
PKC
??????????? AMPA??????
????
5
??????????????

1. ????(PF)?????(CF)???????Ca2??????
2. PF???????CF???????(?????????????????? )
3. Ca2????????LTD??????

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Motivations of Systems Biology Simulation

• Most cerebellar learning theories (including
  Itos) require PF-CF temporal window for
  plasticity (STDP).
• But, some experiments (photolysis, strong PF
  stimulation) are against this temporal window.
  Then, biological significance of LTD?
• How altered synaptic efficacy can be maintained
  in medium term (several tens of minutes)?

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PF?CF????Ca2??
Wang et al., (2000) Nat Neurosci
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Temporal Window of PF and CF Inputs for Ca2
Firing and LTD
Wang et al., (2000) Nat Neurosci 3, 1266-1273
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IP3??????

1. IP3R?????IP3?Ca2??????
2. Ca2?????????

Open Probability
Bezprozvanny et al., Nature(1991)
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A New Model of IP3R based on Adkins and Taylor
Four-States Model
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Ca2 ??????????
PF
Glu
CF
mGluR
AMPA-R
VGCC
PLC
DAG
Gq
Ca2
IP3
IP3R
Ca2Store
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CF??
PF
Glu
CF
mGluR
AMPA-R
VGCC
VGCC
PLC
DAG
Gq
IP3
Ca2
Ca2
IP3R
Ca2Store
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PF?? AMPA-R??
PF
CF
Glu
mGluR
AMPA-R
VGCC
PLC
DAG
Gq
IP3
Ca2
IP3R
Ca2Store
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PF?? mGluR??
PF
CF
Glu
AMPA-R
VGCC
mGluR
PLC
Gq
Ca2
IP3R
Ca2Store
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PF?IP3?????CF???
PF
CF
AMPA-R??
mGluR??
Ca2
?
Positive Feedback Loop
IP3
IP3R
Ca2Store
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?PF?CF??????
PF
CF
AMPA-R??
mGluR??
?
Ca2
Ca2
Positive Feedback Loop
IP3
IP3R
Ca2Store
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?PF?CF??????
PF
CF
AMPA-R??
mGluR??
Ca2
?
Positive Feedback Loop
IP3
IP3R
Ca2Store
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?PF?CF????
PF
CF
AMPA-R??
mGluR??
?
Ca2
Positive Feedback Loop
IP3
IP3R
Ca2Store
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?PF?CF????
PF
CF
AMPA-R??
mGluR??
?
Ca2
Positive Feedback Loop
IP3R
Ca2Store
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????????????
PF
Glu
CF
mGluR
AMPA-R
VGCC
PLC
DAG
Gq
IP3
Ca2
IP3 enzyme
Leak
IP3R
Ca2Buffer Proteins
Ca2Store
Leak
Ca2pump
Ca2pump
Na/Ca2 exchanger
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Signal Transduction Pathways of Supralinear Ca2
Increase
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Simulation of Supralinear Ca2 Increase

• GENESIS simulator with Kinetikit interface
  developed by Upi Bhalla
• Ordinary differential equations for
  molecule-molecule and enzymatic reactions
• 49 variables and 95 parameters
• 20 initial concentrations with 3 assumed
• 25 dissociation constants and Michaelis constants
  with 3 assumed
• 9 maximum enzyme velocities with 3 assumed

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?Glu?mGluR?Gq
Glu
mGluR
Gq
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???????
?????
(1)???????
Kf
AB AB
Kb
dA/dt -KfAB KbAB A AB A all
const.
????KdKb/Kf ???????????? ???t 1/(Kf
Kb)??????????
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???????
?????
(1)???????
Kf
AB AB
Kb
(2)????(Michaelis-Menten)
Kf
Kcat
ES ES EP
Kb
EEnzyme, SSubstrate, PProduct
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(No Transcript)
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Supralinear Ca2 Increase is dependent on PF and
CF Timing
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Temporal Window of Ca2 FiringCoincidence
Detection of PF and CF
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Ca2 Dynamics explains Three Different Forms of
LTD
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Time Delay by IP3 Slow Increase and Coincidence
Detection by IP3R
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??????LTD??
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???????????
????
Glutamate
NO
membrane
Ica
Positive
feedback
loop
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???????????
????
????
AMPA R
membrane
Positive
feedback
loop
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???????????????
????
????
AMPA R
AMPA R
Na/Ca
Na/Ca
membrane
Ica
Ica
2


Ca
Raf
PKC
AA
AA
MEK
MEK
MAP kinase
PLA2
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????(LTD)???
0.5
0.4
????
????
Non-Phosphorylated AMPA Receptors
0.3
AMPA receptor (mM)
0.2
Phosphorylated AMPA Receptors
0.1
Stimulus 1Hz for 5min
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
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AMPA-R?????????
0.15
0.10
PKC concentration (mM)
0.05
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
PKC
AMPA-R
AMPA-R
PP2A
P
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????Ca2?DAG?PKC????
0.15
0.10
PKC concentration (mM)
0.05
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
DAG
PKC
AMPA-R
AMPA-R
PP2A
P
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???AA?PKC??????
0.15
0.10
PKC concentration (mM)
0.05
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
DAG
AA
PKC
AMPA-R
AMPA-R
PP2A
P
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PP2A??????????
0.15
0.10
PKC concentration (mM)
0.05
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
DAG
AA
PKC
AMPA-R
AMPA-R
PP2A
P
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LTD??????Ca2???
3.0
PF CF PF alone CF alone
2.0
Active PP2A (mM)
1.0
0
0
20
40
60
80
100
Time (min)
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?????????
Simulation data
Deleted pathways
0.3
control
0.2
AMPA phosphorylation (mM)
0.1
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
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PKC?????
Simulation data
Deleted pathways
0.3
control
0.2
AMPA phosphorylation (mM)
0.1
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
PKC Block
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NO?LTD???
Simulation data
Deleted pathways
0.3
control
0.2
AMPA phosphorylation (mM)
0.1
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
NO Block
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Ca2?????????
Simulation data
Deleted pathways
0.3
control
0.2
AMPA phosphorylation (mM)
0.1
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
Chelate Ca2
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MAPK??????LTD?????
Simulation data
Deleted pathways
0.3
control
0.2
AMPA phosphorylation (mM)
0.1
0
0
10
20
30
40
50
60
70
80
90
100
Time (min)
Block MAP kinase