Neuroscience study investigating memory deficits and its translation relevance to Schizophrenia Technical and Quantitative Methodologies

1. Behavioural
Neuroscience
School
of
Psychology
Reduced
NRG-­‐1
func:oning
disrupts
the
‘what’
and
‘when’
component
of
an
Episodic
Memory
task
in
TM-­‐
domain
mutants
Mathur
N
,
O’Callaghan
MJ,
O’Tuathaigh
CMP,
Waddington
JL,
Moran
PM
Introduc:on
Results
• A
one
way
ANOVA
showed
no
significant
main
effect
of
• Schizophrenics
show
disrupted
episodic
memory
• WT
mice
showed
increased
explora7on
of
old
objects
compared
to
the
recent
objects
indexed
by
DR
>0.5
(one
genotype
[f(1,27)=
.139,
p>0.05]
or
sex[f(1,27)=
.094,
p>0.05]
on
the
DR
for
sta7onary
vs
displaced
objects.
No
genotype
by
defined
as
memory
for
items
embedded
in
a
sample
T-­‐test
versus
0.5,
P<0.05).
A
significant
sex
by
sex
interac7on
on
the
preference
for
sta7onary
vs
displaced
genotype
interac7on
on
DR
was
found
[f(1,27)=
4.796,
p=. objects
[f(1,27)=
.218,
p>0.05]
was
seen.
spa7otemporal
contexts
(Leavi=,VM
et
al.
2009).
037].
• One
sample
t
tests
(DR<0.05)
indicated
that
neither
WT
[t=
• Neuregulin-­‐1
(NRG1)
is
an
at
risk
haplotype
for
• There
was
a
significant
reduc7on
in
DR
compared
to
WT
[t=
-­‐1.262,
df=15,p>0.05]nor
Het[t=
-­‐.684,
df=14,p>0.05]
animals
showed
an
increased
preference
for
the
displaced
vs
sta7onary
3.680,
df=7,p=.008]in
male
NRG1
(+/-­‐)Het
[t=
2.286,
df=6,p=.
schizophrenia
(Harrisson,
PJ
et
al.,2006).
062]
only
object
• Female
NRG1
(+/-­‐)
mice
showed
significantly
enhanced
DR
[t=
5.026,
df=7,p=.002]
compared
to
WT
li=ermates
.
0.70
• Mutant
mice
heterozygous
(HET)
for
the
NRG1
Discrimination
Ratio
0.70 0.65
gene
or
its
receptor
ErbB4
have
been
shown
to
Discrimination
Ratio
0.65 0.60
display
cogni7ve
deficits
reminiscent
of
those
demonstrated
in
schizophrenia
in
tasks
such
as
working
and
spa7al
memory,
prepulse
inhibi7on
0.60
0.55
0.55
0.50
and
locomotor
ac7vity(O’Tuathaigh,
Harte
et
al.
0.50
0.45
2010,
Duffy
et
al.
2010).
0.45
0.40
0.40 WT
f HET
f WT
m HET
m
WT
f HET
f WT
m HET
m
• We
wanted
to
address
weather
reduced
func7on
Genotype
Genotype
of
the
NRG-­‐1
gene
affect
s
a
complex
what-­‐
Old
vs
New
object
DR
Sta:onary
vs
Displaced
Object
DR
where-­‐when
episodic
memory
task
aspect
Stationary
vs
Displaced
ratio
Stationary vs Displaced ratio: 0.46
relevant
to
schizophrenia,
that
encompasses
a
Stationary vs Displaced ratio: 0.45
Methods
Stationary vs Displaced ratio: 0.45
Stationary vs Displaced ratio: 0.5
temporal
and
a
spa7al
• Object
recogni7on
task
based
on
explora7on
of
objects
in
an
open
field
was
Conclusions
used;
consis7ng
of
2
sample
and
one
test
phase.
See
figure.
• Reduced
func7on
of
TM-­‐NRG1
gene
has
sex-­‐specific
Materials
• In
the
sample
phases,
mice
were
sequen7ally
allowed
to
explore
four
copies
effects
on
episodic-­‐like
memory
• Nrg-­‐1
+/-­‐
mice
were
generated
at
the
Victor
Chang
• Impairments
in
episodic
memory
are
seen
in
males
of
an
object
A
(old
object)
and
an
object
B
(recent
object).
In
the
test-­‐phase,
and
improvements
in
females.
Cardiac
ins7tute
University
of
South
Wales,
animals
were
tested
on
two
copies
of
object
A
(A1
and
A2)
and
two
copies
of
• This
model
may
have
relevance
for
inves7ga7ng
Darlinghurst,
NSW,
Australia
and
then
imported
object
B
(B1
and
B2).
memory
dysfunc7on
in
schizophrenia,
par7cularly
in
from
imported
from
the
Royal
College
of
Surgeons,
Dublin,
Ireland.
the
context
of
sexually
dimorphic
memory
impairment.
• object
A2
was
displaced
to
a
different
loca7on
from
that
used
in
sample-­‐
• Adult
mice
40-­‐44
weeks,
(30
gms),.
phase
1
while
object
A1
remained
at
its
original
posi7on.
Both
Objects
B1
and
• C57BL6
background
strain
mouse;
backcrossed
for
B2
were
le_
at
their
original
posi7ons
as
in
sample
2.
References
• Leavi=,
V.
and
T.
Goldberg
(2009).
"Episodic
Memory
in
Schizophrenia."
14
genera7ons.
Neuropsychology
Review
19(3):
312-­‐323.
• Each
of
the
stages
was
separated
by
a
50min
inter-­‐trial
interval,
and
mice
• Duffy,
L.,
E.
Cappas,
et
al.
(2010).
"Cogni7on
in
transmembrane
domain
allowed
to
explore
objects
for
10min
per
stage.
neuregulin
1
mutant
mice."
Neuroscience
In
Press,
Corrected
Proof.
• HET
TM-­‐NRG1
(NRG1
+/-­‐)
and
wildtype
(WT)
• O’Tuathaigh,
C.
M.
P.,
M.
Harte,
et
al.
(2010).
"Schizophrenia-­‐related
endophenotypes
in
heterozygous
neuregulin-­‐1
‘knockout’
mice."
European
(NRG1
+/+)
male
and
female
li=ermates
were
Journal
of
Neuroscience
31(2):
349-­‐358.
• A
discrimina7on
ra7o
(DR)
was
calculated
as
explora7on
7me
at
old
objects/
generated
from
heterozygous
breeding
pairs
and
•
O'
Tuathaigh,
B.,
D.,
O'
sullivan
G.J.,
Clifford
J.J,
Tighe,
O.,
Croke,
D.T.,
Harvey,R.
7me
spent
at
old+
recent
objects
(A/A+B)
in
the
test-­‐phase
and
as
explora7on
and
Waddington
J.L.
(2007).
"Phenotypic
characteriza7on
of
spa7al
cogni7on
and
genotyped
(O’Tuathaigh
et
al;
2006,
2007b).
social
behaviour
in
mice
with
'knockout'
of
the
schizophrenia
risk
gene
neuregulin
7me
at
old
displaced
objects/7me
spent
at
old
sta7onary+
old
displaced
1."
Neuroscience
147:18-­‐27