stage1 stage2 stage3 stage4 - gunma...
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stage1 stage2 stage3 stage4
20 m
Neuronal Development
20μm
5μm
Mature neuron
Presynaptic axonal terminal
Postsynaptic dendritic spine
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Mature synapse
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脳の最小機能単位シナプス 外界からの刺激
シナプスの応答
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シナプスに記憶される。
(シナプス可塑性)
脳の最小機能単位シナプス 外界からの刺激
シナプスの応答
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Stable actin clustering
PSD95
PSD95 clustering
Spine formation processes
stable actin filaments
dynamic actin filaments
filopodia protospine mature spine
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Dendritic spines
Stubby Mushroom
Thin Wide
Ramified Double
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Spine morphology in the abnormal brain
A.Normal 6 month infant Purpura, 1974B Abnormal 10 month infant (Developmental Disabilities) Purpura,1974C.Abnormal 5.5 month infant (Abnormal behavior) Purpura, et al., 1982D.Fragile X syndrome (adult) Wisniewski, et al., 1991
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Mature synapse
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Discovery of drebrin (1984 )
drebrin A
ADFH CH2(233-317)
Ins2(318-364)
HB1(591-595)CH1(173-227) HB1(675-679)
drebrin
Ca2+ sensor
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EM‐IHC and LM‐IHC images of dendritic spines
DrebrinSynaptophysin
Hayshi and Shirao, J Neurosci, 1996
Drebrin is highly concentrated in dendritic spines in vivo.
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Published in: Shivani Sharma; Elena E. Grintsevich; Martin L. Phillips; Emil Reisler; James K. Gimzewski; Nano Lett. 2011, 11, 825-827.DOI: 10.1021/nl104159vCopyright © 2010 American Chemical Society
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Drebrin-A inhibits F-actin depolymerization and increases the thermal stability of F-actin.
Mikati M A et al. J. Biol. Chem. 2013;288:19926-19938
©2013 by American Society for Biochemistry and Molecular Biology
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Drebrin A‐binding actin filament (DA‐actin) is aslow treadmilling stretched‐helix pitch filament.
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Non-DA-actin(Dynamic actin pool) Spine
Shaft
DA-actin(Stable actin pool)
Resting state LTP induction
Ca2+ entry
NMDAR activation
Facilitation of polymerization
Exod
us
Myosin II activation
Non-DA-actin(Enlargement actin pool)
Ca2+ reduction and/orAMPAR activation ?
Re-entry
LTP maintenance
DA-actin
A B C
Morphological synaptic plasticity
PLoS ONE. 9(1):e85367 (2014)
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Actin filament in non‐neuronal cells
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Actin filament in non‐neuronal cellsneurons
Drebrin
Calcium sensor protein
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正常な一般細胞
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ドレブリンタンパク質を発現した一般細胞
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Discovery of drebrin (1984 )
drebrin A
ADFH CH2(233-317)
Ins2(318-364)
HB1(591-595)CH1(173-227) HB1(675-679)
drebrin
Ca2+ sensor
![Page 22: stage1 stage2 stage3 stage4 - Gunma Universityneuro.dept.med.gunma-u.ac.jp/wp-content/uploads/2014/09/...Spine morphology in the abnormal brain A.Normal 6 month infant Purpura, 1974](https://reader033.vdocuments.site/reader033/viewer/2022041818/5e5c6ba752cbcd73f52db46b/html5/thumbnails/22.jpg)
Non-DA-actin(Dynamic actin pool)
Spine
DA-actin(Stable actin pool)
stable actin
dynamic actin drebrin
elongating actin
NMDAR
AMPARGlu
Ca2+
microtubule
EB3
(rapid treadmiling )
(slow treadmiling )
DA‐actin and Non‐DA‐actin correspond to stableand dynamic actin pool, respectively.
Slow treadmillingactin filaments
Non DA‐actin
DA‐actin
Rapid treadmillingactin filaments
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stage1 stage2 stage3 stage4
F-actin Drebrin
20 m
Actin filaments in growth cone
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GFP‐DE occurred at a speed of about 0.86 ± 0.1 m/min(lower panels), which is similar to that of F‐actin inthe transitionl zone (Medeiros et al. 2006).
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10um
2um 2um
1um 1um
conventional microscope N-STORM
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10um
2um 2um
1um 1um
conventional microscope N-STORM
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Non-DA-actin(Dynamic actin pool)
Spine
DA-actin(Stable actin pool)
stable actin
dynamic actin drebrin
elongating actin
NMDAR
AMPARGlu
Ca2+
microtubule
EB3
(rapid treadmiling )
(slow treadmiling )
DA‐actin and Non‐DA‐actin correspond to stableand dynamic actin pool, respectively.
Slow treadmillingactin filaments
Non DA‐actin
DA‐actin
Rapid treadmillingactin filaments
![Page 28: stage1 stage2 stage3 stage4 - Gunma Universityneuro.dept.med.gunma-u.ac.jp/wp-content/uploads/2014/09/...Spine morphology in the abnormal brain A.Normal 6 month infant Purpura, 1974](https://reader033.vdocuments.site/reader033/viewer/2022041818/5e5c6ba752cbcd73f52db46b/html5/thumbnails/28.jpg)
Drebrin decreases in Alzheimer’s Disease
Western Blotting
Aged control AD
drebrin drebrin
synaptophysin synaptophysin
Immunohistochemistry of Hippocampus
Harigaya et al., J Neurosci Res (1996)
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Drebrin and cognitive activity
Counts et al., J Neuropathol Exp Neurol. 2006
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Non-DA-actin(Dynamic actin pool) Spine
Shaft
DA-actin(Stable actin pool)
Resting state LTP induction
Ca2+ entry
NMDAR activation
Facilitation of polymerization
Exod
us
Myosin II activation
Non-DA-actin(Enlargement actin pool)
Ca2+ reduction and/orAMPAR activation ?
Re-entry
LTP maintenance
DA-actin
A B C
Morphological synaptic plasticity
PLoS ONE. 9(1):e85367 (2014)
![Page 31: stage1 stage2 stage3 stage4 - Gunma Universityneuro.dept.med.gunma-u.ac.jp/wp-content/uploads/2014/09/...Spine morphology in the abnormal brain A.Normal 6 month infant Purpura, 1974](https://reader033.vdocuments.site/reader033/viewer/2022041818/5e5c6ba752cbcd73f52db46b/html5/thumbnails/31.jpg)
stable actin
dynamic actin drebrin
elongating actin
NMDAR
AMPARGlu
Ca2+
microtubule
EB3
(rapid treadmiling )
(slow treadmiling )
LTP induction
Ca2+ entry
NMDAR activation
Facilitation of polymerization
Exod
us
Myosin II activation
Non-DA-actin(Enlargement actin pool)
DA-actin
B
Sekino et al. MCN, 2006Mizui et al. PLoS One, 2014
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Non-DA-actin(Dynamic actin pool) Spine
Shaft
DA-actin(Stable actin pool)
Resting state LTP induction
Ca2+ entry
NMDAR activation
Facilitation of polymerization
Exod
us
Myosin II activation
Non-DA-actin(Enlargement actin pool)
Ca2+ reduction and/orAMPAR activation ?
Re-entry
LTP maintenance
DA-actin
A B C
Morphological synaptic plasticity
PLoS ONE. 9(1):e85367 (2014)
![Page 33: stage1 stage2 stage3 stage4 - Gunma Universityneuro.dept.med.gunma-u.ac.jp/wp-content/uploads/2014/09/...Spine morphology in the abnormal brain A.Normal 6 month infant Purpura, 1974](https://reader033.vdocuments.site/reader033/viewer/2022041818/5e5c6ba752cbcd73f52db46b/html5/thumbnails/33.jpg)
stable actin
dynamic actin drebrin
elongating actin
NMDAR
AMPARGlu
Ca2+
microtubule
EB3
(rapid treadmiling )
(slow treadmiling )
LTP induction
Ca2+ entry
NMDAR activation
Facilitation of polymerization
Exod
us
Myosin II activation
Non-DA-actin(Enlargement actin pool)
DA-actin
B
Drebrin exodus Sekino et al. MCN, 2006Mizui et al. PLoS One, 2014
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stable actin
dynamic actin drebrin
elongating actin
NMDAR
AMPARGlu
Ca2+
microtubule
EB3
(rapid treadmiling )
(slow treadmiling )
LTP induction
Ca2+ entry
NMDAR activation
Facilitation of polymerization
Exod
us
Myosin II activation
Non-DA-actin(Enlargement actin pool)
DA-actin
B
Drebrin exodusPromotion of
actin nucleation
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NMDAR activation
Ca2+ entryMyosin II activation
stable actin
dynamic actin drebrin
elongating actin
NMDAR
AMPARGlu
Ca2+
microtubule
EB3
(rapid treadmiling )
(slow treadmiling )
Resting state Drebrin exodus Promotion of actin nucleation
Reformation of stable actin
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Drebrin content correlates with spine head size.
Kobayashi et al., JCN 2007