Neuropsychopharmacology,
Год журнала:
2024,
Номер
49(11), С. 1758 - 1766
Опубликована: Июнь 19, 2024
Synaptic
plasticity
occurs
via
multiple
mechanisms
to
regulate
synaptic
efficacy.
Homeostatic
and
Hebbian
are
two
such
by
which
neuronal
synapses
can
be
altered.
Although
these
processes
mechanistically
distinct,
they
converge
on
downstream
regulation
of
AMPA
receptor
activity
modify
glutamatergic
neurotransmission.
However,
much
remains
explored
regarding
how
prominent
forms
interact.
Ketamine,
a
rapidly
acting
antidepressant,
increases
transmission
pharmacologically-induced
homeostatic
plasticity.
Here,
we
demonstrate
that
still
intact
in
have
undergone
scaling
ketamine
after
either
systemic
injection
or
perfusion
onto
hippocampal
brain
slices.
We
also
investigated
this
relationship
the
context
stress
induced
chronic
exposure
corticosterone
(CORT)
better
model
circumstances
under
may
used
as
an
antidepressant.
found
CORT
anhedonia-like
behavioral
phenotype
mice
but
did
not
impair
long-term
potentiation
(LTP)
induction.
Furthermore,
does
impact
intersection
mechanisms,
from
CORT-exposed
demonstrated
ketamine-induced
LTP
succession.
These
results
provide
mechanistic
explanation
for
treatment
depression
integrity
learning
memory
encoded
LTP.
Molecular Psychiatry,
Год журнала:
2021,
Номер
27(3), С. 1618 - 1629
Опубликована: Ноя. 24, 2021
Abstract
(
R,S
)-ketamine
elicits
rapid-acting
and
sustained
antidepressant
actions
in
treatment-resistant
patients
with
depression.
R
produces
longer-lasting
effects
than
S
rodents;
however,
the
precise
molecular
mechanisms
underlying
of
remain
unknown.
Using
isobaric
Tag
for
Relative
Absolute
Quantification,
we
identified
nuclear
receptor-binding
protein
1
(NRBP1)
that
could
contribute
to
different
antidepressant-like
two
enantiomers
chronic
social
defeat
stress
(CSDS)
model.
NRBP1
was
localized
microglia
neuron,
not
astrocyte,
mouse
medial
prefrontal
cortex
(mPFC).
increased
expression
NRBP1,
brain-derived
neurotrophic
factor
(BDNF),
phosphorylated
cAMP
response
element
binding
(p-CREB)/CREB
ratio
primary
cultures
thorough
extracellular
signal-regulated
kinase
(ERK)
activation.
Furthermore,
activate
BDNF
transcription
through
activation
CREB
as
well
MeCP2
(methyl-CpG
2)
suppression
microglia.
Single
intracerebroventricular
(i.c.v.)
injection
CREB-DNA/RNA
heteroduplex
oligonucleotides
(CREB-HDO)
or
exon
IV-HDO
blocked
CSDS
susceptible
mice.
Moreover,
microglial
depletion
by
colony-stimulating
receptor
(CSF1R)
inhibitor
PLX3397
In
addition,
inhibition
single
i.c.v.
mannosylated
clodronate
liposomes
(MCLs)
significantly
Finally,
CREB-HDO,
MCLs
beneficial
on
reduced
dendritic
spine
density
mPFC
These
data
suggest
a
novel
ERK-NRBP1-CREB-BDNF
pathways
)-ketamine.
Neuropsychopharmacology,
Год журнала:
2023,
Номер
49(1), С. 41 - 50
Опубликована: Июль 24, 2023
Abstract
Ketamine
is
an
open
channel
blocker
of
ionotropic
glutamatergic
N
-Methyl-
D
-Aspartate
(NMDA)
receptors.
The
discovery
its
rapid
antidepressant
effects
in
patients
with
depression
and
treatment-resistant
fostered
novel
effective
treatments
for
mood
disorders.
This
not
only
provided
new
insight
into
the
neurobiology
disorders
but
also
uncovered
fundamental
synaptic
plasticity
mechanisms
that
underlie
treatment.
In
this
review,
we
discuss
key
clinical
aspects
ketamine’s
effect
as
a
rapidly
acting
antidepressant,
circuit
underlying
action,
well
how
these
perspectives
practice
synapse
biology
form
road
map
future
studies
aimed
at
more
neuropsychiatric
Neuropsychopharmacology,
Год журнала:
2023,
Номер
49(1), С. 51 - 66
Опубликована: Июнь 27, 2023
Abstract
N-methyl-D-aspartate
(NMDA)
receptors
mediate
a
slow
component
of
excitatory
synaptic
transmission,
are
widely
distributed
throughout
the
central
nervous
system,
and
regulate
plasticity.
NMDA
receptor
modulators
have
long
been
considered
as
potential
treatments
for
psychiatric
disorders
including
depression
schizophrenia,
neurodevelopmental
such
Rett
Syndrome,
neurodegenerative
conditions
Alzheimer’s
disease.
New
interest
in
therapeutic
targets
has
spurred
by
findings
that
certain
inhibitors
produce
surprisingly
rapid
robust
antidepressant
activity
novel
mechanism,
induction
changes
brain
well
outlast
presence
drug
body.
These
driving
research
into
an
entirely
new
paradigm
using
antagonists
host
related
conditions.
At
same
time
positive
allosteric
being
pursued
enhancing
function
diseases
feature
hypofunction.
While
there
is
great
promise,
developing
must
also
navigate
significant
risks
posed
use
agents.
We
review
here
emerging
pharmacology
agents
target
different
subtypes,
offering
avenues
capturing
targeting
this
important
class.
Major
depressive
disorder
(MDD)
is
a
highly
prevalent
and
disabling
disorder.
Despite
the
many
hypotheses
proposed
to
understand
molecular
pathophysiology
of
depression,
it
still
unclear.
Current
treatments
for
depression
are
inadequate
individuals,
because
limited
effectiveness,
delayed
efficacy
(usually
two
weeks),
side
effects.
Consequently,
novel
drugs
with
increased
speed
action
effectiveness
required.
Ketamine
has
shown
have
rapid,
reliable,
long-lasting
antidepressant
effects
in
treatment-resistant
MDD
patients
represent
breakthrough
therapy
MDD;
however,
concerns
regarding
its
efficacy,
potential
misuse,
remain.
In
this
review,
we
aimed
summarize
mechanisms
pharmacological
depression.
We
focused
on
fast
treatment
clarified
safety,
tolerability,
ketamine
metabolites
treatment,
along
review
mechanisms,
research
challenges,
future
clinical
prospects.
Annual Review of Neuroscience,
Год журнала:
2022,
Номер
45(1), С. 581 - 601
Опубликована: Май 4, 2022
Depression
is
an
episodic
form
of
mental
illness
characterized
by
mood
state
transitions
with
poorly
understood
neurobiological
mechanisms.
Antidepressants
reverse
the
effects
stress
and
depression
on
synapse
function,
enhancing
neurotransmission,
increasing
plasticity,
generating
new
synapses
in
stress-sensitive
brain
regions.
These
properties
are
shared
to
varying
degrees
all
known
antidepressants,
suggesting
that
synaptic
remodeling
could
play
a
key
role
pathophysiology
antidepressant
function.
Still,
it
unclear
whether
precisely
how
synaptogenesis
contributes
transitions.
Here,
we
review
evidence
supporting
emerging
model
which
defined
distinct
distributed
across
multiple
circuits,
neurons
assuming
altered
functional
properties,
configurations,
and,
importantly,
reduced
capacity
for
plasticity
adaptation.
act
initially
facilitating
enabling
reconfiguration
this
state.
Subsequently,
plays
specific
sustaining
these
changes
over
time.
Nature Communications,
Год журнала:
2022,
Номер
13(1)
Опубликована: Май 12, 2022
Abstract
Ketamine
treatment
decreases
depressive
symptoms
within
hours,
but
the
mechanisms
mediating
these
rapid
antidepressant
effects
are
unclear.
Here,
we
demonstrate
that
activity
of
adult-born
immature
granule
neurons
(ABINs)
in
mouse
hippocampal
dentate
gyrus
is
both
necessary
and
sufficient
for
ketamine.
activates
ABINs
parallel
with
its
behavioral
stressed
unstressed
mice.
Chemogenetic
inhibition
ABIN
blocks
ketamine,
indicating
this
effects.
Conversely,
chemogenetic
activation
without
any
change
neuron
numbers
mimics
cellular
increased
These
findings
thus
identify
a
specific
cell
population
mediates
actions
can
potentially
be
targeted
to
limit
ketamine’s
side
while
preserving
therapeutic
efficacy.
Trends in Molecular Medicine,
Год журнала:
2023,
Номер
29(5), С. 364 - 375
Опубликована: Март 10, 2023
Acute
administration
of
(R,S)-ketamine
(ketamine)
produces
rapid
antidepressant
effects
that
in
some
patients
can
be
sustained
for
several
days
to
more
than
a
week.
Ketamine
blocks
N-methyl-d-asparate
(NMDA)
receptors
(NMDARs)
elicit
specific
downstream
signaling
induces
novel
form
synaptic
plasticity
the
hippocampus
has
been
linked
action.
These
events
lead
subsequent
transcriptional
changes
are
involved
effects.
Here
we
review
how
ketamine
triggers
this
intracellular
pathway
mediate
which
underlies
and
links
it
