Billard, Jean-Marie

Freret, Thomas

Gorisse, L.

Ploux, E

Radzishevsky, I

Wolosker, H

HAL - Normandie Université

A robust link between d-serine and amyloid pathology in a mouse model

Archive Ouverte en Sciences de l'Information et de la Communication

HAL Id: hal-02331029
https://hal-normandie-univ.archives-ouvertes.fr/hal-02331029
Submitted on 24 Oct 2019
HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.
A ROBUST LINK BETWEEN D-SERINE AND
AMYLOID PATHOLOGY IN A MOUSE MODEL
E Ploux, L. Gorisse, I Radzishevsky, H Wolosker, Thomas Freret, Jean-Marie
Billard
To cite this version:
E Ploux, L. Gorisse, I Radzishevsky, H Wolosker, Thomas Freret, et al.. A ROBUST LINK BE-
TWEEN D-SERINE AND AMYLOID PATHOLOGY IN A MOUSE MODEL. 4th International
Conference of D-Amino Acid Research, Sep 2019, Tokyo, Japan. ￿hal-02331029￿
025
50
75
%
 o
f 
ti
m
e
 i
n
 t
h
e
 t
a
rg
e
t 
q
u
a
d
ra
n
t
$ $
$
$
1 2 3 4 5
0
150
300
450
600
750
900
S
w
im
m
in
g
 d
is
ta
n
ce
 (
cm
)
#
*
*
300 400 500
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Stimulus intensity (μA)
ra
ti
o
 f
E
P
S
P
/P
F
V
Eva PLOUX1, Lucile GORISSE1, Inna RADZISHEVSKY2, Herman WOLOSKER2, Thomas FRERET1, Jean-Marie BILLARD1
1Normandie Univ, UNICAEN, INSERM, COMETE, GIP CYCERON, 14000 Caen, France
2Department of biochemistry, Technion, Israel Institute of Technology, Haifa, Israel
Contact: 
eva.ploux@unicaen.fr
A ROBUST LINK BETWEEN 
D-SERINE AND AMYLOID PATHOLOGY IN A MOUSE MODEL
N-methyl-D-aspartate receptor (NMDAr) plays a crucial role in neuronal plasticity and higher brain functions such as memory and learning. Its activation requires, additionally to glutamate, binding of a coagonist, such
as D-serine. NMDAr are affected by the β-amyloid (Aß) pathology and growing number of evidences suggest an involvement of D-serine in plasticity and cognitive-related impairments. Therefore, transgenic 5xFAD
mice (bearing 5 familial Alzheimer disease-linked mutations) which shows accentuated amyloidogenesis, was crossed with mice having a deletion of the gene coding for Serine-Racemase (SR), converting L- into D-serine,
to generate a bigenic line of mice: 5xFAD/SR-/-.
To assess the role of D-serine within Aβ-induced alterations, transgenic lines of mice (10-12 months old) were compared through a combined approach (gathering biochemical analyses, hippocampal-dependent
behavioral tests and extracellular electrophysiological recordings at CA3/CA1 hippocampal synapses).
Biochemical analyses
(N=4-7 per group)
• Hippocampal  Aβ42 level
0
100
200
300
400
500
D
-s
e
ri
n
e
 (
n
m
o
l/
g
)
*
*
*
Slight – but non significant – decrease of Ab42 in bigenic mice 
(compared to 5XFAD)
Of note, higher levels of D-serine were noticeable in 5xFAD mice 
(compared to WT). 
No expression of Serine Racemase in SR-/- and bigenic mice, 
agreeing with the very low level of D-serine in these lines.
Behavior
- N=15-21 per group
- Free exploration in the Y-maze for 8-min
- Successive entries in the 3 arms of the
maze were considered as an alternation
- The percentage of alternation was
calculated as follows: NB of alternations /
(total NB of arms visited – 2) x 100. This
percentage was compared to the chance
value (50%)
SR deletion in the bigenic
reverses working memory deficits 
displayed by 5xFAD mice
• Morris Water Maze
•
Compared to WT mice, 
5xFAD and bigenic mice display reduced spatial learning performances, but unaltered reference memory 
Compared to WT mice, 
5xFAD mice display a flexibility deficit, noticeable during relearning and thus in the probe test. 
Adding SR deletion alleviates this deficit during relearning hence partially reverses reference memory deficits.
Learning
Relearning
Probe-test 1
Probe-test 2
40
45
50
55
60
65
%
 a
lt
e
rn
a
ti
o
n
$
$ $
• Spontaneous alternation test
- Mice (N=16-22 per group) were trained to learn the location of the hidden platform (through distinct visual cues)
- Learning and relearning session: 4 trials of 60 sec / day during 5 days (60 sec inter-trial interval)
- Probe tests: performed 48 after last trial of respectively, learning and relearning session. Platform was removed and mice were free to explore the 
maze during 60 sec 
1 2 3 4 5
0
150
300
450
600
750
900
S
w
im
m
in
g
 d
is
ta
n
ce
 (
cm
)
*
Extracellular recording in CA1 stratum radiatum of hippocampal slices
(after electrical stimulation of Schaffer collaterals)    
Ex vivo electrophysiological recording
- N=10-16 mice per group
- Testing stimulation (average of 3 stimulations at 0,1 Hz) for 15min baseline and then resumed for 60 min after conditioning stimulation
- Conditioning : 1 electrical train at 100 Hz for 1 sec
- N=11-13 mice per group
- Presynaptic Fiber Volley (PFV) and fEPSPs were recorded in low magnesium supplemented medium with the non-NMDAr antagonist NBQX (10µM)
(A): Input/Output graph of fEPSP/PFV ratio
(B): Percentage of increase of fEPSP/PFV ratio (at 400µA) either before and 15 min after addition of D-serine
SR deletion reverses LTP deficits displayed by 5xFAD mice
(A) No genotype difference of NMDAr activation is observed in basal conditions
(B) The increase in NMDAr activation induced by exogenous-D-serine is significantly lower in 5xFAD mice, 
suggesting a decrease in NMDA receptor density, which is reversed when the SR is deleted concomitantly.
100
120
140
160
180
L
T
P
 m
a
g
n
it
u
d
e
 (
%
 o
f 
b
a
s
e
li
n
e
)
*
-15 0 15 30 45 60
100
150
200
250
300
350
Time (min)
 f
E
P
S
P
 s
lo
p
e
 (
%
 o
f 
b
a
s
e
li
n
e
)
#
*
• High frequency stimulation (HFS)-induced long-term potentiation (LTP)
• Isolated NMDAr-mediated fEPSPs (field Excitatory PostSynaptic Potentials)
BA
Altogether, these results highlight critical involvement of D-serine in Aβ-induced hippocampal network dysfunctions and related cognitive disabilities.
(N=4-6 per group)
WT SR-/- 5xFAD 5xFAD/SR-/-
50 ms
0
.2
 m
V
• Hippocampal expression of Serine-Racemase 
and D-serine level
0
10
20
30
40
%
 i
n
c
re
a
s
e
 w
it
h
 e
x
o
g
e
n
o
u
s
 D
-s
e
ri
n
e
*
0.0
0.4
0.8
1.2
1.6
2.0
S
R
 /
 a
c
ti
n
 (
A
U
)
* *
0
40
80
120
160
A
β
4
2
 (
n
g
/m
g
)
0
25
50
75
%
 o
f 
ti
m
e
 i
n
 t
h
e
 t
a
rg
e
t 
q
u
a
d
ra
n
t
$
$
*
1 2 3 4 5
0
150
300
450
600
750
900
S
w
im
m
in
g
 d
is
ta
n
c
e
 (
c
m
)
WT SR-/- 5xFAD 5xFAD/SR-/-
1 2 3 4 5
0
150
300
450
600
750
900
S
w
im
m
in
g
 d
is
ta
n
c
e
 (
c
m
)
WT SR-/- 5xFAD 5xFAD/SR-/-
1 2 3 4 5
0
150
300
450
600
750
900
S
w
im
m
in
g
 d
is
ta
n
c
e
 (
c
m
)
WT SR-/- 5xFAD 5xFAD/SR-/-
1 2 3 4 5
0
150
300
450
600
750
900
S
w
im
m
in
g
 d
is
ta
n
c
e
 (
c
m
)
WT SR-/- 5xFAD 5xFAD/SR-/-
Transgenic mouse line comparison
 Data are expressed in mean + sem
 Univariate t-test: $ p<0.05 vs 50%  § p<0.05 vs 25%   
 ANOVA one-way: * p<0.05 vs WT
 ANOVA repeated measures: # p<0.05 vs WT
#
WT SR-/- 5xFAD 5xFAD/SR-/-


English

A ROBUST LINK BETWEEND-SERINE AND AMYLOID PATHOLOGY IN A MOUSE MODEL

https://hal-normandie-univ.archives-ouvertes.fr/hal-02331029/document

A robust link between d-serine and amyloid pathology in a mouse model

Abstract

Similar works

Full text

Available Versions

HAL - Normandie Université

Archive Ouverte en Sciences de l'Information et de la Communication