Redox imbalance, myelin deficits and impaired cognitive function in a rat model for schizophrenia
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Issue Date
2016-08-01
Language
en
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Abstract
Current
treatments
of
the
neurodevelopmental
disorder
schizophrenia
are
mainly
targeted
against
the
positive
symptoms
of
the
disorder.
The
treatment
of
cognitive
symptoms,
however,
is
still
an
unmet
need.
Moreover,
the
underlying
mechanisms
of
how
these
symptoms
develop
are
not
fully
understood.
Recent
literature
suggests
an
involvement
of
redox
imbalance,
myelin
deficits
and
oligodendrocyte
abnormalities
in
this
process.
Our
hypothesis
poses
that
a
redox
imbalance
might
lead
to
stress
in
oligodendrocytes
and
myelin
deficits,
with
subsequent
cognitive
symptoms.
We
used
the
APO-‐SUS
rat
line
as
a
model
for
schizophrenia,
with
the
APO-‐
UNSUS
counterpart
animals
as
controls.
We
investigated
whether
deficits
in
redox-‐related
gene,
myelin-‐
associated
protein
and
oligodendrocyte
transcription
factor
mRNA
expression
are
present
in
several
brain
regions
of
female
APO-‐SUS
rats
of
pre-‐
and
post-‐adolescent
ages.
In
medial
prefrontal
cortex
and
the
dorsal
striatum
of
female
APO-‐SUS,
myelin-‐
associated
protein
mRNAs
were
down-‐regulated
at
several
ages.
Also
at
these
ages,
mRNAs
of
two
redox-‐related
genes,
Gstm4
and
Prdx6,
showed
dysregulated
expression.
Furthermore,
the
presence
of
cognitive
deficits
in
the
executive
functioning
domain
was
evaluated
by
a
perceptual
discrimination
paradigm
and
the
possibility
for
consequent
remyelination
was
explored
at
the
transcript
level
in
APO-‐SUS
and
APO-‐UNSUS
males.
We
found
that
male
APO-‐SUS
showed
lower
performance
and
faster
inter-‐trial
intervals
after
an
intra-‐dimensional
shift
in
the
perceptual
discrimination
paradigm.
However,
no
increase
in
mRNA
expression
of
myelin-‐associated
proteins
in
the
medial
prefrontal
cortex
was
observed
after
extensive
neuronal
activation.
Lastly,
myelin
deficits
at
different
developmental
time-‐points
were
investigated
at
the
structural
level
in
male
APO-‐SUS
by
Third
Harmonics
Generation
Microscopy
validated
by
immunohistochemistry.
Third
Harmonics
Generation
microscopy
showed
differences
in
third
harmonic
signal
contrast
between
male
APO-‐SUS
and
their
APO-‐UNSUS
counterparts,
and
was
able
to
visualize
the
developmental
event
of
myelination.
Summarizing,
the
present
study
clearly
suggests
a
link
between
redox
imbalance
and
oligodendrocyte
and
myelin
deficits.
Further
studies
into
this
hypothesis
are
necessary
to
aid
in
the
development
of
remyelination
strategies
that
could
ultimately
alleviate
cognitive
symptoms
in
patients
with
schizophrenia.
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