stage1 stage2 stage3 stage4

20 m

Neuronal Development

20μm

5μm

Mature neuron

Presynaptic axonal terminal

Postsynaptic dendritic spine

Mature synapse

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

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

Stable actin clustering

PSD95

PSD95 clustering

Spine formation processes

stable actin filaments

dynamic actin filaments

filopodia protospine mature spine

Dendritic spines

Stubby Mushroom

Thin Wide

Ramified Double

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

Mature synapse

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

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.

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

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

Drebrin A‐binding actin filament (DA‐actin) is aslow treadmilling stretched‐helix pitch filament.

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)

Actin filament in non‐neuronal cells

Actin filament in non‐neuronal cellsneurons   

Drebrin

Calcium sensor protein

正常な一般細胞

ドレブリンタンパク質を発現した一般細胞

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

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

stage1 stage2 stage3 stage4

F-actin Drebrin

20 m

Actin filaments in growth cone

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).

10um

2um 2um

1um 1um

conventional microscope N-STORM

10um

2um 2um

1um 1um

conventional microscope N-STORM

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

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)

Drebrin and cognitive activity

Counts et al., J Neuropathol Exp Neurol. 2006 

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)

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

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)

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

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 

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

Drebrin content correlates with spine head size.

Kobayashi et al., JCN 2007