Abstract |
The
prefrontal
cortex
(PFC)
is
involved
in
higher-‐order
cognitive
functions
(short-‐term
and
long-‐term
mnemonic
functions)
as
well
as
in
emotional
processes.
Although
age
seems
to
play
a
significant
role
in
both
the
normal
function
of
PFC
and
the
emergence
of
disease
states,
very
little
is
known
with
regards
to
the
age-‐dependent
changes
of
behaviors
involving
the
PFC
and
the
underlying
cellular
mechanisms.
Previous
studies,
primarily
based
on
dendritic
morphology,
have
suggested
that
this
higher-‐order
brain
region
exhibits
delayed
cortical
development
compared
to
primary
sensory
cortical
areas
that
lasts
until
young
adulthood.
Investigating
the
PFC
postnatal
development
is
critical
to
radically
improve
our
understanding
of
brain
function
and
behavior
as
well
as
of
the
emergence
substrate
of
devastating
neuropsychiatric
disorders
involving
the
PFC.
The
PFC,
similar
to
other
cortical
areas,
is
composed
of
glutamatergic
excitatory
neurons
and
GABAergic
inhibitory
interneurons.
A
balance
between
these
two
systems
is
required
for
proper
functioning
of
the
PFC.
Recently,
the
role
of
the
GABAergic
system
has
strongly
been
implicated
in
contributing
to
possible
imbalances
between
the
two
main
systems,
ultimately
leading
to
pathological
states.
Our
goal
in
this
dissertation
was
two-‐fold.
Firstly,
we
aimed
to
better
understand
the
postnatal
development
of
the
PFC
and
secondly,
to
study
changes
in
PFC
behavior
and
underlying
cellular
mechanisms
in
cases
with
reduced
GABAergic
inhibition.
Our
results
are
presented
in
three
different
chapters.
In
Chapter
I,
we
used
a
multidisciplinary
approach
including
cellular,
electrophysiological
and
behavioral
techniques
in
different
age
groups
of
mice
in
order
to
better
understand
the
PFC
development.
In
many
cases,
a
comparison
to
other
cortical
areas
was
made.
We
find
a
differential
expression
of
distinct
types
of
dendritic
spines
in
pyramidal
neurons
of
PFC
between
different
age
groups
of
mice.
In
particular,
‘adolescent’
pyramidal
neurons
(40
days
old)
exhibit
the
lowest
spine
density
measured,
with
an
increased
percentage
of stubby
spines,
while
the
‘juvenile’
(35
days
old)
and
‘young
adult’
pyramidal
neurons
(60
days
old)
have
increased
number
of
spines,
and
particularly
of
the
mushroom
type.
This
developmental
pattern
was
also
observed
in
our
electrophysiological
studies,
in
which
the
‘juvenile’
and
‘young
adult’
age
groups
exhibit
increased
long-‐term
potentiation
(LTP)
of
synaptic
transmission
in
response
to
tetanic
stimulation,
while
the
‘adolescent’
age
group
exhibits
decreased
LTP.
Finally,
‘adolescent’
mice
perform
poorer
in
PFC-‐dependent
tasks,
such
as
the
delayed
alternation
in
the
T-‐maze
and
the
temporal
order
object
recognition
task,
without
exhibiting
differences
in
non-‐PFC-‐dependent
tasks,
such
as
the
novel
object
and
objet-‐to-‐place
recognition
tasks,
compared
to
young
adult
mice.
In
Chapter
II,
we
studied
the
role
of
decreased
inhibition
in
PFC
physiology
and
in
mouse
behavior,
using
the
Rac1
conditional
transgenic
mouse
(Rac1
cKO)
that
displays
~50%
less
cortical
interneurons
due
to
the
loss
of
the
Rac1
protein
from
Nkx2.1-‐expressing
cells.
We
find
that
the
adult
Rac1
cKO
exhibit
increased
susceptibility
to
pharmacological-‐induced
epileptic
seizures
as
well
as
increased
anxiety.
At
the
cellular
level,
Rac1
cKO
mice
exhibit
impaired
short-‐term
plasticity
and
LTP
in
response
to
tetanic
stimulation
within
the
PFC.
Changes
in
dendritic
morphology,
such
as
reduced
mushroom-‐type
spines
and
reduced
dendritic
length,
could
underlie
the
decrease
in
LTP
of
the
Rac1
cKO
mice.
In
Rac1
cKO
brain
slices,
up-‐regulation
of
GABA-‐receptor-‐mediated
neurotransmission
using
a
mild
dose
of
diazepam
was
sufficient
to
rescue
the
impaired
LTP.
The
above
findings
led
us
to
further
hypothesize
that
the
PFC
network
of
Rac1
cKO
mice
exhibit
an
imbalance
of
excitation
and
inhibition,
caused
by
deregulation
of
the
glutamatergic
system
in
response
to
functional
reductions
of
the
GABAergic
system,
which
ultimately
result
in
increased
anxiety
and
vulnerability
to
epileptic
seizures.
We
also
studied
the
juvenile
Rac1
cKO
mice,
which
exhibit
decreased
anxiety
and
increased
LTP
induction
after
tetanic
stimulation
with
an
underling
increase
in
the
number
of
dendritic
spines
compared
to
juvenile
Rac1
Het (heterozygous)
mice,
used
as
control.
Finally,
acute
or
chronic
inhibition
of
the
GABAergic
system
in
Rac1
Het
mice
with
picrotoxin
also
impaired
the
LTP
in
the
PFC.
Our
results
suggest
that
proper
inhibition
during
the
juvenile
period
is
critical
for
the
normal
development
of
synaptic
properties
and
plasticity
within
layer
II
of
PFC,
as
well
as
for
the
development
of
the
normal
behavior
and
cognitive
functions.
In
Chapter
III,
we
undertook
a
computational
approach
to
study
how
reductions
in
GABAergic
inhibition
in
a
PFC
microcircuit
model
affect
the
properties
of
persistent
activity,
considered
the
cellular
correlate
of
working
memory
function
in
PFC.
To
this
end,
we
constructed
a
PFC
microcircuit,
consisting
of
pyramidal
neuron
models
and
all
three
different
types
of
interneurons:
fast-‐spiking
(FS),
regular-‐spiking
(RS),
and
irregular-‐spiking
(IS)
interneurons.
Persistent
activity
was
induced
in
the
microcircuit
model
and
its
properties
were
analyzed.
Removing
or
decreasing
the
FS
model
input
to
the
pyramidal
neuron
models
greatly
limited
the
biophysical
modulation
of
persistent
activity
induction,
decreased
the
ISIs
(inter-‐spike
intervals),
neuronal
synchronicity
and
gamma-‐power
oscillations
during
persistent
activity.
The
effect
on
synchronicity
and
oscillations
could
be
reversed
by
the
addition
of
other
inhibitory
inputs
to
the
soma,
but
beyond
the
levels
of
the
control
network.
Thus,
generic
somatic
inhibition
acts
as
a
pacemaker
of
persistent
activity
and
FS
specific
inhibition
modulates
the
output
of
the
pacemaker.
Overall,
our
results
contributed
to
the
growing
knowledge
on
PFC
functions
during
development
and
their
underlying
mechanisms
that
render
the
PFC
“the
region
that
humans
prize
for
its
ability
to
regulate
our
thoughts
and
behaviors”.
|