Brain Research Institute
Niigata University

Annual Report 2017Preventive medicine for Alzheimers disease
KWEE, Ingrid L.
Elucidation of the roles of chromatin remodeler in neuronal homeostasis using mouse models
FUTAI, Kensuke
Research on pathway-specific control of motor activity and motor- and reward-related learning
behaviors via dopamine D1 and D2 receptors
D1 D2
WANG, Yanyan30

3

31

100

(1)
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Namba H, Nagano T, Jodo E, Eifuku S, Horie M, Takebayashi H, Iwakura Y, Sotoyama H, Takei N, Nawa
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Furukawa K, Fuse I, Iwakura Y, Sotoyama H, Hanyu O, Nawa H, Sone H, Takei N. Advanced glycation
end products induce brain-derived neurotrophic factor release from human platelets through the Src-family
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(1)

(2)

(3)

(4)

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31

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123

26

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proliferation and chain migration in the adult brain. Eur J Neurosci. 2017 Sep;46(6):2214-2228.
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trafficking in mice deficient in the kinase activity of PKN1. Sci Rep. 2017 Aug 9;7(1):7663.
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The BRI International Symposium 2018

Saturday, February 10

10:00

Opening Remarks Hiroyuki Nawa (Director, BRI, Niigata University)

10:10

Integral system by CAST/ELKS protein family to regulate retinal photoreceptor development andmaintenance

Chairedby
AkiyoshiKakita&Katsuei
ShibukiToshihisa Ohtsuka (University of Yamanashi)

Molecular mechanisms underlying neuronal homeostasis
Kensuke Futai (University of Massachusetts Medical School, USA)

Anayasis of Autism Susceptibility Candidate 2 (AUTS2) gene during development
Mikio Hoshino (National Institute of Neuroscience, National Center of Neurology and Psychiatry)

Clustered protocadherins regulate complex neural networks
Takeshi Yagi (Osaka University)

13:10

Complement family proteins bridge over troubled synapses

ChairedbyMechanisms of activity-dependent synapse elimination in the developing cerebellum

Hiroyuki
Nawa

Michisuke Yuzaki (Keio University)
Masanobu Kano (The University of Tokyo)

Molecular mechanisms for cerebellar circuitry refinement
Masahiko Watanabe (Hokkaido University)

15:00
ChairedbyTakeshi
IkeuchiMechanism that arrests myelin regeneration in chronic demyelinated lesions
Kazuhiro Ikenaka (National Institute for Physiological Sciences)

Molecular machinery for controlling synaptic transmission
Susumu Tomita (Yale School of Medicine, USA)

16:10

Poster Session

17:30

Reception ()

Sunday, February 11

09:00
Chairedby
Masaki
Ueno

Unraveling the regulatory mechanisms for hypothalamic corticotropin-releasing factor neurons
using novel mouse lines
Keiichi Itoi (Tohoku University)

Regulatory mechanism of sleep/wakefulness and memory
Akihiro Yamanaka (Nagoya University)

Molecular integration of circadian clocks in mammals
Hitoshi Okamura (Kyoto University)

10:50
ChairedbyToshikuni

Sasaoka

Cell-type-specific STORM super-resolution of synaptic endocannabinoid signaling in the
hippocampus
István Katona (Institute of Experimental Medicine (KOKI), Hungarian Academy of Sciences (MTA), Hungary)

Development of gene manipulation methods for animal models, mouse, rat and marmoset, for the
analysis of brain function
Kenji Sakimura (BRI, Niigata University)

13:00

Dopaminergic memory enhancement by two distinct novelty systems

ChairedbyArc-haeology of learning and memory

KazukiTainaka

Tomonori Takeuchi (Aarhus University, Denmark)Haruhiko Bito (The University of Tokyo)

Axon growth and regeneration regulated by extracellular and intracellular signals
Michihiro Igarashi (Niigata University)

14:50
Chairedby
Hironaka
Igarashi

15:50

Paternally inherited transgenerational epigenome changes to understand neurodevelopmental
disorders
Noriko Osumi (Tohoku University)

Disease modeling and brain mapping using genetically modified marmosets
Hideyuki Okano (Keio University)

Closing Remarks Kenji Sakimura (BRI, Niigata University)

Contact noukyoudo@adm.niigata-u.ac.jp025-227-0565

29

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F.
1.
1) Ishii T, Kawakami E, Endo K, Misawa H, Watabe
K. Formation and spreading of TDP-43 aggregates incultured neuronal and glial cells demonstrated bytime-lapse imaging. PLoS One 2017;12:e0179375.
2) Ishii T, Kawakami E, Endo K, Misawa H, Watabe
K. Myelinating coculture of rodent stem cellline-derived neurons and immortalized Schwann cells.
Neuropathology 2017;37:475-481.
3) Yanagisawa H, Ishii H, Endo K, Kawakami E,
Akiyama K, Watabe K, Komatsu M, Yamamoto D,
Eto Y. L-leucine and SPNS1 coordinately ameliorate
dysfunction of autophagy in mouse and humanNiemann-Pick type C disease. Sci Rep 2017;7:15944.
4) Niimi N, Yako H, Takaku S, Kato H, Matsumoto T,
Nishito Y, Watabe K, Ogasawara S, Mizukami H,
Yagihashi S, Chung SK, Sango K. A spontaneously
immortalized Schwann cell line from aldose reductasedeficient mice as a useful tool for studying polyol
pathway and aldehyde metabolism. J Neurochem
2018;144:710-722.
2.
1)

TDP-43
HSF1

TDP-4358

HSP70, DNAJB2a/b, HSPB8, HSPH3

cDNA
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ALS

TDP-432017 6 3 .
2) Watabe K, Kato Y, Murata M, Sakuma M,
Niida-Kawaguchi M, Kakita A, Shibata N. Heat shock
response suppresses adenovirus-induced TDP-43
aggregate formation in cultured neuronal cells. XXIIIWorld Congress of Neurology, Kyoto, September 19,
2017.
3) Shibata N, Niida-Kawaguchi M, Kato Y, Noguchi N,
Kakita A, Watabe K. Soluble iron accumulation makes
microglia to overproduce and release glutamate via
aconitase 1, TACE and glutaminase C in ALS spinal
cords. XXIII World Congress of Neurology, Kyoto,
September 19, 2017.

4)
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10.3389/fneur.2018.00173
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2. Verheijen BM, Hashimoto T, Oyanagi K, van

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intracytoplasmic inclusions immunoreactive for

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G-PDC-ALS

G-PDC
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ALS
G-ALS

G-PDC

1. Verheijen BM, Oyanagi K, van Leeuwen FW.
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29

1
2
1

2

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A.

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(0.875 g/

1

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1 g)

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EGF
(EGF: 8.6 ± 0.2 days,

control: 14.6 ± 0.2 days)
10-11
2017.12.16,
EGF(0.5-1.5 Hz)
VOR

OKR
D.
EGF
EGF gene

SNP(Anttila 2004)
EGF(Futamura 2002)

EGF

EGF
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EGF

EGF
30

E.
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F.
1.

2.

C57BL/6

G.

1. Katano, T., Fukuda, M., Furue, H., Yamazaki, M.,
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, 3(5) e0110-16, 118, 10, 2016

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82018 22.
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Identification

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BEGAINcharacterization

guanylate,ofkinase-associatedprotein as a neuropathic pain-related protein in
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7

40

C

2

flox

Cre

DNA

B.

MTA

loxP

the midline barrier for proper corticospinal axonCre

37 32 , 7682-99. (2017)

guidance.

flox
Cre

2

Katori, S., Noguchi-Katori, Y., Okayama, A.,
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GFPCre-loxP

layer

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GFP

transmitted

via

thalamocortical

22(1), 123-135. (2018)

H. Mizuno., K. Ikezoe., T. Sato., K. Kitamura.,

T. Iwasato.

4
Barrel-confined patchwork

activity of the somatosensory layer 4 neurons
in neonates.
40
(

2017

7

20-23

)

S. Katori., Y. Noguchi-Katori., S. Itohara., T.
Iwasato.
Midline barrier for axon guidance is protectedby EphA4 -chimaerin signaling in the spinal
cord.
40

2017
2017

7

7

20-23

,

19

(

)

S. Nakazawa., T. Iwasato.
4in vivo
Katori, S., Noguchi-Katori, Y., Itohara, S., Iwasato, T.
Spinal RacGAP -chimaerin is required to establish

Three-day-long invivo imaging of dendritic reorganization inbarrel cortex layer 4 in neonates.
40
(

)

2017

7

20-23

Neuroscience Program of Academia Sinica

5
2017

8

29

-8

30

2017
12

2

2017

9

7

-9

12

8

2017

9

23

-9

-24
H. Mizuno., K. Ikezoe., T. Sato., K. Kitamura., T.
Iwasato.
Patchwork-type spontaneous activity in layer 4of neonatal barrel cortex transferred via
thalamocortical projections
Society for Neuroscience 2017, 11

11

-15

,

(Washington, DC)
S. Nakazawa., H. Mizuno., T. Iwasato.
Three-day-long in vivo imaging of dendritic
reorganization in barrel cortex layer 4 inneonatesSociety for Neuroscience 2017, 11

11

-15

,

(Washington, DC)

Unveiling the mechanisms of neuronal circuit
refinement in the neonatal mouse barrel Cortex
Academia Sinica Symposium, 2017
,

(

)

11

27

16

(

)

GluD1

GluD1

B.

GluD
GluD2

GluD1
in situ
GluD1

C.

GluD1
2014

in situ

GluD1
DLG

GluD1 mRNA
(VGluT1) mRNA

1

VGluT2 mRNA
GluD1
GluD1

DLG

VGluT2(VAChT)

VGluT2

VAChT

VPM

GluD1

VGluT2

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D.
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2
30

E.
GluD1

cholinergic neurostimulating peptide:HCNP

Hippocampal

A

ASPD

ASPD
Na, K-ATPase

Noguchi. JBC2009
NAK 3

3

Ohnishi. PNAS2015
NAK 3

ALS
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NAK 3
ASPD

ASPD

ASPD

ADNI

ASPD

PET

A
mylospheroid
Noguchi

ASPD, JBC2009

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Na, K-ATPase

3

NAK 3
Ohnishi. PNAS2015
NAK 3

ASPD
ASPD

NAK 3

NAK 3
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NAK 3

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NAK 1

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ALS
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in situ

ALS

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NAK 3
in situ

NAK 3

NAK 3

NAK 1

ASPD

NAK 3

NAK 3
NAK 3

Distinct cellular distribution of alpha subunit
isoforms of Na, K ATPase in the mouse brain. (inpreparation)

Na+, K+-ATPase3 is a Death Target of Alzheimer
Amyloid- Assembly What Shall We Do Next
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Na+, K+-ATPase
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Minako HOSHI, The 15th International
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2017

2

21

(Nishiyama Y et al.

2002

29

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hybridization

VGF
ALS

VGF mRNAVGF mRNA

neurofilament heavy

VGF mRNAVGF mRNA

ALS

ALS

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VGF
A.

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Amyotrophic lateralsclerosis: ALS
90%

10%
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VGF(SOD1)(2) ALS
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ALS
hybridization

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VGF
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ALS

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B.
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)

9

ALS

ALS

3

(

4 m)

RNAscope®

9

human VGF

hybridizationneurofilament heavy

neurofilament heavy

(NFH)

VGF

mRNA

hybridization

Scale bar = 50 µM

PBS
Wash

10% Goat serum

1
PBS

(

)
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SMI-32, Merck Millipore)
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(FV10i; Olympus)
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ALS

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F.

mRNA

Control

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ALS

1.

(

)

2.

G.
1.
2.

[
VGF mRNA]

1: Zhao Z. et al., Vgf is a novel biomarker
associated with muscle weakness in amyotrophic
lateral sclerosis (ALS), with a potential role in disease
pathogenesis. Int J Med Sci. 2008 Apr 15;5(2):92-9.

Scale bar = 100 µM

2: Noda Y., VGF and striatal cell damage in in vitroand in vivo models of Huntington's disease.
Pharmacol Res Perspect. 2015 Jun;3(3):e00140. doi:
10.1002/prp2.140.
3: Shimazawa M. et al., An inducer of VGF
protects cells against ER stress-induced cell death andprolongs survival in the mutant SOD1 animal models
of familial ALS. PLoS One. 2010 Dec 9;5(12):e15307.

AD (LOAD)

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. (2017).

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Brain and Nerve. 69(7):835-842
2.
. (2017)

LOAD 38

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28(7):754-765

1.

,

,

,

,

,

,

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,

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3.

Masataka

Kikuchi,Norikazu

Hara,

Mai

Hasegawa, Akinori Miyashita, Ryozo Kuwano,Takeshi Ikeuchi, and Akihiro Nakaya. The
prediction method of deleterious variants for
Alzheimer's

diseaseusing

chromatin

higher-order structure. Alzheimer's Association
International ConferenceAAIC

16-20 London, United Kingdom.

2017. July

fMRI
10

fMRI
free timing

timingcued timing

cued

free timing

15

15

free timing

fMRI

10Hz

1

Honami Sakata, Kosuke Itoh, Yuji Suzuki, Katsuki
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10timingfree

Honami Sakata, Kosuke Itoh, Yuji Suzuki,
Katsuki Nakamura, Masaki Watanabe, Hironaka
Igarashi, Tsutomu Nakada Endogenously
initiated movements are preceded by neuralactivities in multiple cortical regions: an
event-related fMRI study. 47th Annual meetingof Society for Neuroscience, Washington D.C.,
November 2017.

(AD)

(DS)
pSNCA

pSNCA

(pSNCA)
AD

pSNCA

A

(PD)

(LBD)
LBD

Sample
i)

ii)

(AD)

AD

pSNCA

AD

(pSNCA)

(DS)

iii)

iv)

1

ApoE genotype
AD

ApoE genotype

DLB
DS

pSNCA
1

pSNCA

DS

1

4
4

AD

SNCA

pSNC

SNCA

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SI, Kondo T, Waki M, Hayasaka T, Masaki

APOE3/4 type

N, Akatsu H, Hashizume Y, Yamamoto S,
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Decreased 16:0/20:4-phosphatidylinositol
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8)

CCE

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Matsuo K, Shindo A, Niwa A, Tabei KI,
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LC-MS/MS

42
14

Ayaki T, Maki T, Sawamoto N, Takahashi
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LC-HR/MS

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LC-MS/MS

42
14

58
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2017
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24

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28
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24

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300 500 mg
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261(10) 969-975,2017.
2.
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GFAP
GFAP

VEGF
1

59(12)
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K,

Ichikawa-Tomikawa

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GFAP

Takahashi H, Kakita A, Imura T, Chiba
H.PKA activation and endothelial claudin-5

GFAP
pH,

EGFR

(PMI),,
28

IL-10 IL17A
3
IP-10(p=0.032)

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.

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,

,2017/9/29

.

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.
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cortical modulation of thalamic neurons. Hirai D,
Nakamura KC, Shibata KI, Tanaka T, Hioki H,
Kaneko T, Furuta T. Brain Struct Funct. 2018
Mar;223(2):851-872.

29

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Neurology

2017Joint Usage / Research Report FY 2017
The Collaborative Research Center for Brain Diseases Utilizing Neuropathological Resources
Brain Research Institute, Niigata University

Preventive medicine for Alzheimers disease
Ingrid L Kwee1

Principal Investigator
Co-Investigator

Hironaka Igarashi2

1 Neurology, University of California Davis 2 BRI, University of Niigata
Abstract
Late onset Alzheimers disease (LOAD) should be prevented rather than treated when cognitive decline isestablished. We have clarified that debris clearance from the brain can be profoundly affected by water dynamics
through the aquaporin 4 (AQP4) system, the astrocyte abundant water channel, and that perturbation in the AQP4
system plays a role in the pathogenesis of LOAD.
To seek out application of newly developed AQP4 modulators for LOAD, we will utilize high-throughput invivo MR method developed at the Center for Integrated Human Brain Science, Brain Research Institute forscreening of drugs. Next, we will perform detailed animal studies to assess these effects on an Alzheimers diseaseanimal model.

A. INTRODUCTION

The purpose of the research is to seek out
applications of newly developed aquaporin
modulators for Alzheimers disease in human, we willtake newly developed high-throughput in vivo MR
methods [1] for selection of candidate compounds.
Next we will assess the effect of chronic
administration of these compounds on an Alzheimer
mouse model.
[1] Igarashi H, Tsujita M, Kwee IL, Nakada T. Water
influx into cerebrospinal fluid is primarily controlled
by aquaporin-4, not by aquaporin-1: 17O JJVCPE
MRI study in knockout mice. Neuroreport. 2014 Jan
8;25(1):39-43

B. MATERIALS AND METHODS

We will use high-throughput in vivo JJVCPE MR
method developed in Center for Integrated Human
Brain Science, Brain Research Institute for screeningof drugs. Candidate drugs will be administeredfollowing best effect protocol. Then MRI experiments
will be performed on a 15 cm bore 7 T horizontal
magnet (Magnex Scientific, Abingdon, UK) with a
Varian Unity-INOVA-300 system (Varian Inc., Palo
Alto, CA, USA) equipped with an actively shielded
gradient. Normal saline, 0.2 ml, containing 20% of
H2(17)O is to be administered as an intravenous bolus
injection at the 75th phase (10 minutes after the firstscan) using an automatic injector at 0.04 ml/second.
Data will be analyzed using software developed at theCenter to assess the efficiency of water metabolism.

C. RESULTS

We have developed candidate small molecules,
which effectively facilitate the water transport of
AQP4 in living mice brain [2].
[2] Huber VJ, Igarashi H, Ueki S, Kwee IL, Nakada
T.Aquaporin-4
facilitator
TGN-073
promotesinterstitial fluid circulation within the blood-brain
barrier: [17O]H2O JJVCPE MRI study. Neuroreport.
2018 Mar 20. doi: 10.1097/WNR.0000000000000990.
[Epub ahead of print]

D. DISCUSSION

We have developed the AQP4 facilitators. Thesemolecules can be effective not only LOAD, but alsodiseases having something to do with brain water
dynamics.

E. CONCLUSION

We developed the first AQP4 facilitator in the world.

F. PUBLICATIONS

Huber VJ, Igarashi H, Ueki S, Kwee IL, Nakada T.
Aquaporin-4 facilitator TGN-073 promotesinterstitial fluid circulation within the blood-brain
barrier: [17O]H2O JJVCPE MRI study.
Neuroreport. 2018 Feb 27.
Sakata H, Itoh K, Suzuki Y, Nakamura K, Watanabe
M, Igarashi H, Nakada T. Slow Accumulations of
Neural Activities in Multiple Cortical Regions
Precede Self-Initiation of Movement: An

Event-Related fMRI Study. eNeuro. 2017 Oct
30;4(5).
Natsumeda M, Motohashi K, Igarashi H, Nozawa T,
Abe H, Tsukamoto Y, Ogura R, Okada M,
Kobayashi T, Aoki H, Takahashi H, Kakita A,
Okamoto K, Nakada T, Fujii Y. Reliablediagnosis of IDH-mutant glioblastoma by
2-hydroxyglutarate detection: a study by 3-T
magnetic resonance spectroscopy. Neurosurg Rev.
2017 Sep 27.
Nakada T, Kwee IL, Igarashi H, Suzuki Y.
Aquaporin-4 Functionality and Virchow-RobinSpace Water Dynamics: Physiological Model for
Neurovascular Coupling and Glymphatic Flow.
Int J Mol Sci. 2017 Aug 18;18(8). Review.
Suzuki Y, Nakamura Y, Yamada K, Kurabe S,
Okamoto K, Aoki H, Kitaura H, Kakita A, Fujii Y,
Huber VJ, Igarashi H, Kwee IL, Nakada T.
Aquaporin Positron Emission Tomography
Differentiates Between Grade III and IV Human
Astrocytoma. Neurosurgery. 2017 Jun 21.
Shimizu M, Suzuki Y, Yamada K, Ueki S, Watanabe
M, Igarashi H, Nakada T. Maturational decreaseof glutamate in the human cerebral cortex fromchildhood to young adulthood: a 1H-MR
spectroscopy study. Pediatr Res. 2017
Nov;82(5):749-752.
Takado Y, Terajima K, Shimohata H, Nakayama H,
Watanabe M, Okamoto T, Ozawa T, Nishizawa
M, Kwee IL, Igarashi H, Nakada T. Sleep Apnea
in Multiple System Atrophy of Cerebellar Type:
A 3.0 T MRS/Volumetry Pilot Study,
eNeurologicalSci. 2016 Oct 11;6:6-8.

G.

APPLICATION AND REGISTRATIONSTATUS ON INTELLECTUAL PROPERTYRIGHTS
1. PATENT
Int. Patent, filing No. PC-23387

Joint Usage / Research Report FY 2017
The Collaborative Research Center for Brain Diseases Utilizing Neuropathological Resources
Brain Research Institute, Niigata University

Elucidation of the roles of chromatin remodeler in neuronal homeostasis using mouse models
Principal Investigator Kensuke
Co-Investigator

Futai1

Kenji Sakimura2

1 Dept. Neurobiology, Univ. Massachusetts Medical School, Brudnick Neuropsychiatry Research Institute,
2 Niigata University, Brain Research Institute

Abstract
Malfunction of neuronal excitatory and inhibitory balance (E/I balance) causes Runaway Network Excitation in
the brain that induces epilepsy and neuronal cell death. Neuronal functions are associated with epigenetic
mechanisms that regulates gene expression without altering DNA sequence, but the association of E/I balancewith epigenetics still needs to be addressed.
Based on our preliminary data from next generation transcriptome profiling of activity-induced neurons andmouse models, we have proposed that the chromatin reader proteins, MBT (malignant brain tumor) andBromodomain proteins, play critical role in homeostatic plasticity.
In this proposal, we will elucidate the epigenetic regulatory mechanisms that prevent runaway excitation andmaintain E/I balance by generating mouse models. Alteration of neuronal homeostasis underlies manyneurological disorders, including epilepsy, autism spectrum disorders, schizophrenia and Alzheimers disease.
Therefore, elucidation of MBT and boromodomain protein-mediated epigenetic regulatory mechanisms will
provide a better understanding of the pathophysiology of neurological disorders and will likely identify novel
therapeutic targets.
During the last year, we have started generating Baz1a flox mouse line. Baz1a is one of the bromodomain
proteins and has been suggested as a risk factor of neurodevelopmental disorder, William Syndrome. During thelast grant period, we established ES cell lines. Currently, we have been working on generating Baz1a chimeralines. We expect to obtain F1 line by the end of 2018. By using this line, we will generate cell type-specific Baz1aknockout mice lines by crossing cre reporter lines. We consider that elucidation of Baz1a function can help toidentify the pathophysiological hallmarks of neurodevelopmental disorder.

A. INTRODUCTION

Runaway excitation of neuronal circuits induces
epileptic seizures, leading to other detrimental
consequences, including neuronal cell death. Neurons
possess homeostatic mechanisms that compensate foractivity perturbations and maintain the excitatory andinhibitory balance (E/I balance). Synaptic scaling is a
specific form of homeostatic plasticity that maintains
proper neuronal excitability via bidirectional
regulation of synaptic strength of a neuron. Both
excitatory and inhibitory synaptic strength are
regulated by scaling mechanisms through changes in
the abundance (scale) of postsynaptic receptors.

Importantly, homeostatic synaptic plasticity
requires activity-dependent transcriptional andtranslational machineries. However, the roles of
epigenetic factors, particularly chromatin regulators,
in this plasticity is largely unknown. Over two
hundred chromatin regulators have been identified in
mammals and are sub-classified by function (e.g.,
readers, erasers or writers of histone modifications,etc.). However, to the best of our knowledge, there are
no reports describing a systematic analysis ofchromatin regulators for potential roles in synaptic
scaling.

Recently, we demonstrate that L3mbtl1, one of
the chromatin reader proteins, regulates basal synaptictransmission and homeostatic plasticity. Importantly,
L3mbtl1 protein binds to the transcription start sites ofCtnnb1 and Gabra2, whose products mediatehomeostatic synaptic scaling and inhibitory synaptictransmission, respectively. These results provide novel
insight as to the roles of a chromatin reader moleculein synaptic function and neuronal homeostasis. During
the course of this project, we identified that achromatin reader molecule, Baz1a, is increased its
expression in an activity-dependent manner. Baz1a
has been suggested as a risk factor ofneurodevelopmental disorder, William Syndrome, andelucidation of Baz1a function can help to identify thepathophysiological hallmarks of this disorder. To
further study the role of Baz1a in synaptic function
and animal behavior, we have started establishing thecell type-specific Baz1a knockout mouse models.

B. MATERIALS AND METHODS

Animals: All animal protocols were approved by theInstitutional Animal Care and Use Committee(IACUC) of the University of Massachusetts Medical
School and Niigata University (PMID: 29398357 and29034317). L3mbtl1 mutant mice were generated
previously and backcrossed with C57BL/6 for four
generations. C57BL/6 mice were also used for RNA
sequencing and primary cultures.
RNA Extraction and RNA sequencing: Total RNA
was extracted from hippocampus or hippocampal
primary cultures using RNAqueous Micro Kits
(Ambion). Sequencing libraries were preparedaccording to ScriptSeq v2 protocol following rRNA
depletion (RiboZero, Illumina), and run on single-end
50-bp modules in Illumina HiSeq 2000.
Primary culture preparation: Primary hippocampal
cultures were prepared from early postnatal (P0-1)
mouse as described previously with somemodifications (Futai et al., 2013). Briefly,
hippocampal neurons were dissociated and plated onto
coverslips coated with poly-D-lysine and laminin.
Neurons were maintained in B27 supplement
containing medium for 14-16 days in vitro (DIV).
C. RESULTS
To date, over 40 genes have been reported as
regulators of homeostatic up- and down-scaling in
hippocampal and cortical neurons. Because theexpression of many of these genes changes during
induction and expression of the scaling, wehypothesized that chromatin regulator molecules,
whose expression is altered by neuronal activity,
contribute to homeostatic synaptic scaling. To test thishypothesis, we performed unbiased transcriptome
analysis by RNA-sequencing of cultured primaryneurons after induced homeostatic down-scaling.
Hippocampal primary cultures were preparedfrom C57BL6 mice and homeostatic synaptic scaling
was induced by applying picrotoxin (PTX), a

non-competitive GABAAR blocker, for 15 hours at
DIV14. Total RNA isolated from Control and PTX
challenged samples was subjected to an unbiased
transcriptome (RNA-Seq) screen. RNA-seq was
performed in quadruplicate for each treatment and theresults were highly clustered into two treatmentgroups. Using stringent criteria, we identified 1150
and 689 of up- and down-regulated genes, respectively.
Multiple genes previously identified as neuronal
activity-dependent, including Arc, Bdnf, Plk2, andHomer1, showed a significant change from baseline in
our transcriptome profiling, confirming the validity of
our system (blue symbols in Fig. 1A). Importantly, 12
out of 246 chromatin regulatory genes showedchanges in mRNA expression (Fig. 1B). In particular,
L3mbtl1 and Baz1a mRNA expression were decreased
and increased to 30 and 631% of control value, as the
top ranking down- and up-regulated molecules
amongst chromatin regulatory genes, respectively (Fig.
1B, blue symbols).
If down-regulation of L3mbtl1 RNA and protein
is part of an essential switch to induce homeostaticsynaptic down-scaling, then L3mbtl1 KO neurons
may exhibit smaller basal synaptic transmission andlack homeostatic plasticity. To test this possibility, we
prepared hippocampal primary and slice cultures fromwild type and L3mbtl1 KO mice and comparedamplitudes and frequencies of miniature excitatory
postsynaptic currents (mEPSCs). Interestingly, we
found that L3mbtl1 KO neurons showed smallermEPSC amplitudes than that of wild type (Fig. 2A),
suggesting that the lack of L3mbtl1 reduces thenumber of AMPARs per synapse. We then studied
L3mbtl1 deficiency in homeostatic plasticity by
application of PTX. Most importantly, L3mbtl1 KO
cultured neurons failed to induce homeostatic
down-scaling by PTX treatment, whereas wild typeneurons could induce down-scaling (Fig. 2).
Furthermore, genome-scale mapping of L3mbtl1

occupancies identified Ctnnb1 as a key genedownstream of L3mbtl1. Importantly, the occupancyof L3mbtl1 on the Ctnnb1 gene was regulated byneuronal activity. L3mbtl1 knockout neurons
exhibited reduced Ctnnb1 expression. Partial
knockdown of Ctnnb1 in wild type neurons reduced
excitatory synaptic transmission and abolishedhomeostatic down-scaling; while transfecting Ctnnb1
in L3mbtl1 knockout neurons enhanced synaptictransmission and restored homeostatic down-scaling.
These results highlight a unique role for L3mbtl1 in
regulating homeostasis of synaptic efficacy. Currently,
we resubmitted these findings to Cell Reports (Seesection F. Publication below).
To further extend our findings, we have decided
to elucidate the role of Baz1a in scaling and animal
behavior. Drs. Sakimura and Abe have started
generating Baz1a flox mouse line at BRI, Niigata
Univ., in summer 2017. ES cell lines that carry floxed
alleles have been established. We expect to generatechimera mice within 2  3 months. By using the
Baz1a flox line, we will generate cell type-specificBaz1a knockout mouse models during the upcoming

Fig. 2 L3mbtl1 is required for homeostatic plasticity during
activity elevation in hippocampal primary (A) and organotypic(B) cultures. Mean mEPSC amplitude of control (DMSO) andPTX-treated neurons from wild-type and L3mbtl1 KO mouse
cultures. N = 11-19 cells. * p<0.05, **** p<0.0001, 2 way

grant year.

D. DISCUSSION

The number of neurotransmitter receptors locatedpostsynaptically is dynamically regulated throughmany different mechanisms. Homeostatic synaptic
scaling is one of the most important regulatory
mechanisms of synaptic strength that prevents the
detrimental consequences of runaway neuronalover-excitation. In the present study, we found thatneuronal activity down-regulates the chromatin reader
molecule, L3mbtl1. Hippocampal primary neurons
prepared from L3mbtl1 KO mice showed a lack ofhomeostatic down-scaling and reduced amplitude of
AMPAR current in excitatory synapses. Moreover,L3mbtl1 KO neurons in organotypic hippocampal
neurons specifically abolished down-scaling withoutchanging basal transmission, supporting theimportance of L3mbtl1 in homeostatic down-scalingof synaptic strength. Our ChIP-seq and ChIP-qPCR

studies identified Ctnnb1 and Gabra2 genes asactivity-dependent targets of L3mbtl1 protein. Ctnnb1
expression is reduced in L3mbtl1 KO, partial KD of
Ctnnb1 causes a lack of homeostatic down-scaling,
and transfection of Ctnnb1 into L3mbtl1 KO neurons
restores homeostatic down-scaling, suggesting that
L3mbtl1 controls synaptic strength through Ctnnb1.
Our results highlight a critical role for theactivity-regulated chromatin reader molecule,
L3mbtl1, in homeostatic control of synaptic strengthand adds to our understanding of epigenetic
mechanisms of activity-dependent gene regulation.
E. CONCLUSION
Our discovery of L3mbtl1 as an activity-dependent
chromatin reader that coordinates the homeostatic
control of synaptic strength raises the intriguing
possibility that other chromatin regulators and theirdownstream genes are required for homeostaticsynaptic plasticity. Elucidating the roles of the otherchromatin regulator, Baz1a, in synaptic plasticity
coupled with our results presented here will provide acomprehensive view of epigenetic regulation of gene
expression in homeostatic synaptic scaling. During thenext grant period, we will establish Baz1a flox mouseline and start crossing cre-reporter lines to generate
cell type-specific Baz1a knockout mouse lines.
F. PUBLICATIONS
1. Activity-induced Epigenetic Regulation of
Synaptic Strength through the Chromatin Reader,
L3mbtl1, Wenjie Mao, Anna C. Salzberg, Motokazu
Uchigashima, Yuto Hasegawa, Hanno Hock,
Masahiko Watanabe, Schahram Akbarian, Yuka
Imamura, and Kensuke Futai, Cell Reports,
Resubmitted
2. Luciferase shRNA presents off-target effects on
voltage-gated ion channels in mouse hippocampal
pyramidal neurons, Yuto Hasegawa, Sucharita Saha,
Georgia Gunner, Jenya Kolpakova, Gilles Martin,
Kensuke Futai, eNeuro (2017), PMID: 29034317,
PMCID: PMC5635487, Published in 2017
3. The inflammasome-derived cytokine IL18
suppresses amyloid-induced seizures in Alzheimersprone mice, Te-Chen Tzeng, Yuto Hasegawa, Daniel R.
Caffrey, Elizabeth Jeanne Thatcher, Weniie Mao, Gail
Germain, Nelsy DePaula Tamburro, Michael Heneka,
Eicke Latz, Kensuke Futai* and Douglas T.
Golenbock*, *Corresponding authors, PNAS, underrevision status
G. PRESENTATIONS
1. Symposium Organizer and Speaker, The 40th
Annual Meeting of The Japan Neuroscience Society,Chiba, Japan, March 20-23, 2017, Symposium Title
Epigenetic Regulation and Dysregulation in
Neurodevelopment
2. Invited
Symposium
Speaker,The
8thInternational Symposium: The innovative progress ofneuroscientific research through the use of advanced
animal models, Niigata, Japan, Feb. 10-12, 2018,
Presentation
Title
Molecular
Mechanisms

Underlying Neuronal Homeostasis
3. Invited speaker, Brain Research Institute, Niigata
Univ., Niigata, Japan, July 14, 2017 Epigenetic
regulation of homeostatic synaptic plasticity throughchromatin reader L3mbtl1
Invited speaker, UT Southwestern, Texas, April
16, 2018, Epigenetic Regulation of homeostatic
plasticity
H. APPLICATION AND REGISTRATIONSTATUS ON INTELLECTUAL PROPERTYRIGHTS
None.
I. OTHERSNone.

Joint Usage / Research Report FY 2017
The Collaborative Research Center for Brain Diseases Utilizing Neuropathological Resources
Brain Research Institute, Niigata University

Research on pathway-specific control of motor activity and motor- and reward-related
learning behaviors via dopamine D1 and D2 receptors
YanYan Wang1

Principal Investigator
Co-Investigator

Toshikuni Sasaoka2

1 Department of Medical Information Science, College of Medicine, Carl R. Woese Institute for Genomic Biology,
University of Illinois at Urbana-Champaign, USA,2 Department of Comparative & Experimental Medicine, Brain Research Institute, Niigata University
Abstract
We have made progress in three aspects of our collaborative research project. First, in collaboration with Prof.
Sasaoka, Prof. Sakimura and Assoc. Prof. Abe group, we have made progress in making the D2S conditional KO
mouse using the new RNA splicing and Cre-loxP recombination method. The process of making the constructionof targeting vector is going well, and the targeting vector will be soon transfected into ES cells, which will be used
to produce chimeric mice. Second, using conditional D1R knockdown and conventional D1R knockout mice, Prof.
Sasaoka group has discovered that the time of eliminating D1R expression affects the behavioral phenotypes withrespect to motor activity. Third, we have made progress in establishing the condition and protocol for studying
neuronal excitability in KO mice using electrophysiological recordings in brain slices. Together, we strive to makecontributions to a better understanding of the neurobiological mechanisms of D1R- and D2R-mediateddopaminergic transmission and their roles in neuropsychiatric disorders.

A. INTRODUCTION

The dopaminergic transmission in the striatum and its
projection areas plays an important role in motor
control, reward, and learning. The striatal efferents are
divided into two main pathways: one is the direct
pathway (projections from the striatum to thesubstantia nigra), which is mediated by the dopamine
D1 receptor (D1R), and another is the indirect
pathway (projections from the striatum to the globus
pallidus), which is mediated by the dopamine D2
receptor (D2R). Two isoforms of D2R: termed D2L(long form) and D2S (short form), have been
identified in the brain of rodents and humans. Our
research proposal is focused on delineating the role of
D1R and individual D2R isoforms in motor andlearning functions and in the pathophysiology ofneuropsychiatric disorders such as schizophrenia andParkinsons disease.

Previously, we generated D2L knockout (KO) mice.
Our studies have demonstrated that the D2L KO
mouse provides a valuable model system to enable us
to begin to investigate the distinct role of individual
D2R isoforms in the mammalian central nervous
system (CNS). However, if we also have D2S KO
mice, this series of research would be greatly
strengthened.

B. MATERIALS AND METHODS

We are collaborating with Prof. Sasaoka, Prof. Kenji
Sakimura and Assoc. Prof. Manabu Abe group to
generate D2S conditional KO mice. We takeadvantage of the new method using RNA splicing andCre-loxP recombination to produce the conditional
KO of D2S, as described in Hayashi et al. (MolecularBrain, 2014, 7:44). In this way, before Cre-loxP
recombination the mice will express both D2S and
D2L receptors. By the Cre-loxP recombination theexons coding D2S and D2L will be changed to themutated exon coding only D2L.

C. RESULTS

Prof. Sasaoka group investigated the role of D1R in
motor activity using conditional D1R knockdown(KD) and conventional D1R KO mice. They examined
the motor behaviors of D1R KD, D1R KO, and WT
mice using the balance beam test and open field test.

A multidisciplinary approach is used including
molecular genetic technology, behavioral tests,
immunohistochemistry, and electrophysiologicalrecordings.

They found that mice with D1R expression eliminatedat the adolescent to adult stages displayed hypoactivity,
whereas mice lacking of D1R at the initialdevelopmental stage displayed hyperactivity (Okubo
et al. 2018).
To study the modulation of neuronal excitability andsynaptic transmission and plasticity by D1R and D2R
isoforms, we are working on the condition andprotocolforperforming
electrophysiologicalrecordings in medium spiny neurons (MSNs) in the
striatum. Figure 1 shows action potentials recorded in
MSNs from the striatum of WT and D2L KO mice in
response to the injection of depolarized currents using
whole-cell patch-clamp recordings. This procedure isnecessary for studying neuronal excitability.

D. DISCUSSION

In collaboration with Drs. Sasaoka, Sakimura and Abegroup, we have made progress in making the D2S
conditional KO mouse. Dr. Abe has informed us thatthe construction of targeting vector is going well, andthey will produce the mutated ES cell using thetargeting vector. We anticipate the process of
producing chimeric mice will be going smoothly using
the ES cell.
The study by Prof. Sasaoka group indicates that thetime of eliminating D1R expression affects the
behavioral phenotypes with respect to motor activity
examined.
We have made progress in studying neuronal
excitability, and will work on establishing thecondition and protocol for studying synaptic plasticity
in KO mice using electrophysiological recordings.

E. CONCLUSION

In summary, we have made progress in three aspectsof our collaborative project, as described above. We
look forward to continuing our collaborative research.

F. PUBLICATIONS

1. PAPERS
Shioda N, Yabuki Y, Wang YY, Uchigashima M,
Hikida T, Sasaoka T, Mori H, Watanabe M, Sasahara
M, Fukunaga K (2017) Endocytosis following
dopamine D2 receptor activation is critical forneuronal activity and dendritic spine formation via
Rabex-5/PDGFR signaling in striatopallidal medium

spiny neurons. Molecular Psychiatry 22:1205-1222.
Sotoyama H, Iwakura Y, Oda K, Sasaoka T, Takei N,
Kakita A, Enomoto H, Nawa H (2017) Striatal
hypodopamine phenotypes found in transgenic micethat overexpress glial cell line-derived neurotrophic
factor. Neuroscience Letters 654:99-106.
Sakagami H, Katsumata O, Hara Y, Sasaoka T, Fukaya
M (2017) BRAG2a, a guanine nucleotide exchange
factor for Arf6, is a component of thedystrophin-associated glycoprotein complex at thephotoreceptor terminal. Investigative Ophthalmology
and Visual Science (IOVS) 58(9):3795-3803.
Fukai Y, Ohsawa Y, Ohtsubo H, Nishimatsu S,
Hagiwara H, Noda M, Sasaoka T, Murakami T,
Sunada Y (2017)
Redundancy of matrix
metalloproteinases
cleaving
beta-dystroglycan:
Implications
forthepathogenesisofsarcoglycanopathy. Biochem Biophys Res Comm 492(2):199-205.
Min E, Ban S, Wang YY, Popescu G, Popescu C-B,
Jung W (2017) Multispectral scattering properties ofbrain tissue. Biomedical Optics Express 8:1763-1770.
Okubo T, Sato A, Okamoto H, Sato T, Sasaoka T(2018) Differential behavioral phenotypes of
dopamine D1 receptor knockdown mice at theembryonic, postnatal, and adult stages. International
Journal of Developmental Neuroscience 66:1-8.
2. PRESENTATIONSInstitute for Genomic Biology, University of Illinois at
Urbana-Champaign, June 2017
School of Pharmaceutical
University, China, Nov. 2017

Sciences,

Beijing
Research
InstituteofPharmaceutical Co., China, Dec. 2017

Shenzhen
Zhendong

College of Life Science and Technology, Huazhong
Agricultural University, China, Dec. 2017G.

APPLICATION AND REGISTRATIONSTATUS ON INTELLECTUAL PROPERTYRIGHTS
1. PATENT
None
2. UTILITY MODEL REGISTRATION
None
3. OTHERS
None

552017.11.11,

UFM1
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Nahorski MS, Maddirevula S, Ishimura R, Alsahli S, Brady AF, Begemann A, Mizushima T, Guzmán-Vega
FJ, Obata M, Ichimura Y, Alsaif HS, Anazi S, Ibrahim N, Abdulwahab F, Hashem M, Monies D, Abouelhoda M,
Meyer BF, Alfadhel M, Eyaid W, Zweier M, Steindl K, Rauch A, Arold ST, *Woods CG, *Komatsu M,*Alkuraya FS. Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
141: 1934-1945 (2018)