HAL Id: hal-02330837
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Submitted on 24 Oct 2019
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Impact of d-serine depletion in the β-amyloid cascade related to Alzheimer’s disease
T. Freret, E Ploux, L. Gorisse, I Radzishevsky, H Wolosker, Jean-Marie Billard
To cite this version:
T. Freret, E Ploux, L. Gorisse, I Radzishevsky, H Wolosker, et al.. Impact of d-serine depletion in theβ-amyloid cascade related to Alzheimer’s disease. Annual Meeting of the Society for Neuroscience (SFN), Oct 2019, Chicago, United States. �hal-02330837�
50 ms 0.2 mV
SR deletion reverses LTP deficits displayed by 5xFAD mice
- Mice 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: 48 after last trial of learning and relearning session and mice were free to explore the maze without platform during 60 sec
T. FRERET 1 , E. PLOUX 1 , L. GORISSE 2 , I. RADZISHEVSKY 3 , H. WOLOSKER 4 , J.-M. BILLARD 1
1 Normandie Univ, UNICAEN, INSERM, COMETE GIP CYCERON, 14000 Caen, France
2 INSERM, Paris, France
3 Department of biochemistry, Technion, Israel Institute of Technology, Haifa, Israel
IMPACT OF D-SERINE DEPLETION IN THE β-AMYLOID CASCADE RELATED TO ALZHEIMER’S DISEASE
Contact information:
thomas.freret@unicaen.fr
Altogether, these results highlight critical involvement of D-serine in Aβ-induced hippocampal network dysfunctions and related cognitive disabilities.
Hippocampal expression
of Serine-racemase and D-serine level
cv
D-serine, as a co-agonist of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR), is a key regulator of their activation. Hence, D-serine is involved in functional brain plasticity and memory processes. In the course of Alzheimer’s disease (AD), homeostasis of NMDA receptors is precociously affected by beta-amyloid peptides (Aβ). However, while early functional dysregulations of NMDAR are well known, contribution of D-serine in early phases of the pathology remains so far to be determined. To this end, we compared behavioral performances and hippocampal synaptic functioning (extracellular electrophysiological recordings) in the well-known 5xFAD transgenic mice model of amyloidogenesis (bearing 5 familial Alzheimer disease-linked mutations), having or not a depletion for serine-racemase gene (allowing D-serine synthesize). Adequate control groups (WT and serine-racemase KO mice) were also performed.
3-4 months old
n = 3-7 per group
Hippocampal Aβ 42 level
3-4 months old
n = 8-16 per group
5xFAD and 5xFAD/SR-/- display similar hippocampal level of Aβ 42
(only traces were observed in WT and SR -/- mice) No significant difference levels of D-serine were
noticeable in 5xFAD mice (compared to WT).
0.0 0.5 1.0 1.5 2.0
S R / a c ti n ( A U )
* *
cv
Behavior
10-12 months old
n = 15-22 per group
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
§ §
§
§
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
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
§
§
*
cv
Morris-water-maze
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 )
*
BIOCHEMICAL ANALYSES
Extracellular recording in CA1 stratum radiatum of hippocampal slices (after electrical stimulation of Schaffer collaterals)
High frequency stimulation (HFS)-induced long-term potentiation (LTP)
(1x100Hz)
300 400 500
0.0 0.5 1.0 1.5
Stimulus intensity (μA)
ra ti o f E P S P /P F V
A
Isolated NMDAR-mediated fEPSPs (field Excitatory Post-Synaptic Potentials)
(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 NMDAR density, which is reversed when the SR is deleted concomitantly.
0 10 20 30 40 50
% 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
B
*
100 110 120 130 140 150
L T P m a g n it u d e ( % o f b a s e li n e )
*
0 100 200 300 400 500
D -s e ri n e ( n m o l/ g )
* *
0 500 1000 1500
A β 4 2 ( p g /m g )
*
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 )
#
*
*
#
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 300µA) either before and 15 min after addition of D-serine - Exploration in the Y-maze for 8-min
- Alternation = successive entries in the 3 arms
- Percentage of alternation
(compared to the chance value 50%) NB of alternations / (total NB of arms visited – 2) x 100
Spontaneous alternation
40 45 50 55 60 65
% a lt e rn a ti o n
$ $ $
SR deletion in the bigenic mice
reverses working memory deficits
displayed by 5xFAD mice
A
B C
WT SR -/- 5xFAD 5xFADSR -/-
All data expressed as 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
#
-15 0 15 30 45 60
100 150 200 250 300
Time (min)
f E P S P s lo p e ( % o f b a s e li n e )
0.2 mV50 ms
