Billard, Jean-Marie

Bouet, V.

Boulouard, M.

Freret, T.

Menager, F

Percelay, Solenn

English

HAL - Normandie Université

Altering glutamate transmission in combination with an early post-natal stress to mimic schizophrenia in male and female mice

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Submitted on 14 Nov 2019
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Altering glutamate transmission in combination with an
early post-natal stress to mimic schizophrenia in male
and female mice
F Menager, Solenn Percelay, T. Freret, M. Boulouard, Jean-Marie Billard, V.
Bouet
To cite this version:
F Menager, Solenn Percelay, T. Freret, M. Boulouard, Jean-Marie Billard, et al.. Altering glutamate
transmission in combination with an early post-natal stress to mimic schizophrenia in male and female
mice. Journée Normande de Recherche Biomédicale, Nov 2019, Caen, France. ￿hal-02363095￿
Altering glutamate transmission in combination with an early post-natal stress
to mimic schizophrenia in male and female mice
F. Menager, S. Percelay, T. Freret, M. Boulouard, JM. Billard, V. Bouet
Normandie Univ, UNICAEN, INSERM, COMETE, GIP CYCERON, 14000 Caen, France
Treatments: not efficient on negative and cognitive 
symptoms, multiple side-effects
Crucial need to refine treatments
 Improving validity of animal models of schizophrenia
 Combining genetic x environmental factors
Maternal separation
PND9-24h
Ellenbroek et al., 1998; Bouet et al., 2011
Total Serine 
racemase deletion
Coyle et al., 2018 x
Schizophrenia 
1% population, onset 15-25 years
Multifactorial: genetic x environmental factors
Symptoms: positive, negative, cognitive
Debilitating disease heavy costs
Behavioural testing
 Anxiety-like behavior
 Short and long-term memory
 Social behavior
 Sensory-motor gating
C57Bl6 male and female mice
Altered glutamate transmission:
 Serine racemase KO mice SRKO
Early stress:
 Maternal separation MS
SR KO  Locomotor activity in all experiments
 Place recognition
 Social recognition
Place recognition
Prepulse Inhibition
Maternal separationSR KO
 Activity 
 Social recognition in male mice
Working memory in female mice
 PPI in female mice
 Anxiety-related behavior
 Place recognition performances
 Object recognition performances in female mice
 Neophobia in males
Maternal
separation
1-hit
SR
1-hit
MS
2-hit
5 min
Short-term memory
Spontaneous alternation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Control MS SR MSxSR Control MS SR MSxSR
Male Female
# #
#
#
#
# #
# univariate t-test >50% n=10-16
MSxSR combination induced working memory deficit
in female but not in male mice
2h
20s / 10min 20s / 10min
Object recognition memory
0
2
4
6
8
10
12
14
16
18
20
Control MS SR MSxSR Control MS SR MSxSR
Male Female
# # # # # # #
Place recognition memory
 Object recognition: MSxSR combination altered
performances in female mice
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Control MS SR MSxSR Control MS SR MSxSR
Male Female
#
Alternation percentage
Time on novel object Discrimination index [(New-Fam)/(New+Fam)]
# univariate t-test >10 n=10-16
Social behavior
Sociability: 10min Social recognition: 10min
Index (mouse vs empty) Index (novel vs familiar mouse)
# # # #
# # # # #
#
P=0.1 # # #
# univariate t-test >0 n=10-16
Sensorimotor gating
pulse prepulse + pulse
Weight (g)
Inhibition
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Control MS SR MSxSR Control MS SR MSxSR
Male Female
76 dB 80 dB 84 dB
MS decreased PPI in female mice
*
x
Summary of the results
2-hit animal models gathers several deficits considered as hallmarks of schizophrenia.
Serine racemase deletion induces an increase in activity, promotes social memory troubles, and contributes 
to a higher sensitivity to maternal separation.
Maternal separation mostly contributes to sensorimotor gating deficits.
2-hit model differentially affect males and females.
Because some deficits (working memory, object recognition, social recognition) appears only in 2-hit mice, 
combining factors may help in improving validity of animal models of schizophrenia. 
Moreover, combining factors reveals differences between males and females, probably accounting for gender 
vulnerability/resilience differences. 
 Place recognition: MSxSR combination altered
performances in male mice
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Control MS SR MSxSR Control MS SR MSxSR
Male Female
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Control MS SR MSxSR Control MS SR MSxSR
Male Female
SR and MSxSR alter social recognition in male mice
5 min 2 min
Inhibition of startle reflex
1h
* p<0,05 : Test U de Mann-Whitney n=10-16
# univariate t-test ≠ 0 n=10-16


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Altering glutamate transmission in combination with an early post-natal stress to mimic schizophrenia in male and female mice

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