medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 21, 2024
Abstract
Background
Preclinical
evidence
suggests
that
diazepam
enhances
hippocampal
γ-aminobutyric
acid
(GABA)
signalling
and
normalises
a
psychosis-relevant
cortico-limbic-striatal
circuit.
Hippocampal
network
dysconnectivity,
particularly
from
the
CA1
subfield,
is
evident
in
people
at
clinical
high-risk
for
psychosis
(CHR-P),
representing
potential
treatment
target.
This
study
aimed
to
forward-translate
this
preclinical
evidence.
Methods
In
randomised,
double-blind,
placebo-controlled
study,
18
CHR-P
individuals
underwent
resting-state
functional
magnetic
resonance
imaging
twice,
once
following
5mg
dose
of
placebo.
They
were
compared
20
healthy
controls
(HC)
who
did
not
receive
diazepam/placebo.
Functional
connectivity
(FC)
between
subfield
nucleus
accumbens
(NAc),
amygdala,
ventromedial
prefrontal
cortex
(vmPFC)
was
calculated.
Mixed-effects
models
investigated
effect
group
(CHR-P
placebo/diazepam
vs.
HC)
condition
placebo)
on
CA1-to-region
FC.
Results
placebo
condition,
showed
significantly
lower
CA1-vmPFC
(
Z
=3.17,
P
FWE
=0.002)
CA1-NAc
=2.94,
=0.005)
FC
HC.
increased
=4.13,
=0.008)
individuals,
both
normalised
HC
levels.
contrast,
HC,
CA1-amygdala
contralaterally
higher
ipsilaterally
conditions
(lower:
=3.46,
=0.002,
=3.33,
=0.003;
higher:
=4.48,
<0.001,
=4.22,
<0.001).
Conclusions
demonstrates
can
partially
restore
dysconnectivity
suggesting
modulation
GABAergic
function
might
be
useful
group.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(12), С. 6521 - 6521
Опубликована: Июнь 13, 2024
Glutamate
is
the
main
excitatory
neurotransmitter
in
brain
wherein
it
controls
cognitive
functional
domains
and
mood.
Indeed,
areas
involved
memory
formation
consolidation
as
well
fear
emotional
processing,
such
hippocampus,
prefrontal
cortex,
amygdala,
are
predominantly
glutamatergic.
To
ensure
physiological
activity
of
brain,
glutamatergic
transmission
finely
tuned
at
synaptic
sites.
Disruption
mechanisms
responsible
for
glutamate
homeostasis
may
result
accumulation
excessive
levels,
which
turn
leads
to
increased
calcium
mitochondrial
abnormalities,
oxidative
stress,
eventually
cell
atrophy
death.
This
condition
known
glutamate-induced
excitotoxicity
considered
a
pathogenic
mechanism
several
diseases
central
nervous
system,
including
neurodevelopmental,
substance
abuse,
psychiatric
disorders.
On
other
hand,
these
disorders
share
neuroplasticity
impairments
areas,
accompanied
by
structural
remodeling
neurons.
In
current
narrative
review,
we
will
summarize
role
both
pathophysiology
therapeutic
interventions
neurodevelopmental
adult
mental
with
focus
on
autism
spectrum
disorders,
drugs
under
preclinical
clinical
development
treatment
different
that
dysfunctions.
Although
evidence
still
limited
more
studies
required,
regulation
attracting
attention
potential
crucial
target
control
diseases.
Pharmacological Research,
Год журнала:
2025,
Номер
unknown, С. 107690 - 107690
Опубликована: Март 1, 2025
Schizophrenia
is
a
severe
and
debilitating
psychiatric
disorder
that
profoundly
impacts
cognitive,
emotional,
social
functioning.
Despite
its
devastating
personal
societal
toll,
current
treatments
often
provide
only
partial
relief,
underscoring
the
urgent
need
for
innovative
therapeutic
strategies.
This
review
explores
emerging
approaches
target
complex
neurobiological
underpinnings
of
schizophrenia,
moving
beyond
traditional
dopamine-centric
models.
Among
these,
some
novel
drugs
still
employ
multimodal
mechanisms,
simultaneously
targeting
dopaminergic
serotonergic
systems
to
enhance
efficacy
tolerability.
Given
well-documented
excitatory/inhibitory
imbalance
in
significant
efforts
have
been
directed
toward
addressing
NMDA
receptor
hypofunctionality.
However,
strategies
this
pathway
yet
demonstrate
consistent
clinical
efficacy.
In
contrast,
therapies
cholinergic
system
shown
greater
promise.
For
instance,
xanomeline-trospium
combination,
which
modulates
muscarinic
receptors,
has
recently
gained
approval,
other
molecules
with
similar
mechanisms
are
currently
under
development.
Beyond
these
approaches,
being
explored
pathways,
including
neuroplasticity,
neuroinflammation,
mitochondrial
dysfunction.
These
designed
as
part
combinatorial
strategy
available
antipsychotic
drugs.
progress,
challenges
remain
translating
experimental
discoveries
into
effective
applications.
Future
research
should
prioritize
biomarker-driven
precision
medicine
optimize
individualized
treatment
outcomes.
By
integrating
targets,
schizophrenia
may
evolve
more
comprehensive
personalized
approach,
disorder's
full
spectrum
symptoms
improving
patient
quality
life.
Translational Psychiatry,
Год журнала:
2025,
Номер
15(1)
Опубликована: Янв. 24, 2025
Abstract
Schizophrenia
spectrum
disorders
(SSD)
involve
disturbances
in
the
integration
of
perception,
emotion
and
cognition.
The
corticolimbic
system
is
an
interacting
set
cortical
subcortical
brain
regions
critically
involved
this
process.
Understanding
how
neural
circuitry
molecular
mechanisms
within
may
contribute
to
development
not
only
positive
symptoms
but
also
negative
cognitive
deficits
SSD
has
been
a
recent
focus
intense
research,
as
latter
are
adequately
treated
by
current
antipsychotic
medications
more
strongly
associated
with
poorer
functioning
long-term
outcomes.
This
review
synthesises
developments
examining
dysfunction
pathophysiology
SSD,
on
neuroimaging
advances
related
novel
methodologies
that
enable
data
across
different
scales.
We
then
integrate
these
findings
inform
identification
therapeutic
preventive
targets
for
symptomatology.
A
range
pharmacological
interventions
have
shown
initial
promise
correcting
improving
negative,
treatment-resistant
symptoms.
discuss
challenges
opportunities
still
limited
translation
research
into
clinical
practice.
argue
our
knowledge
role
can
be
improved
combining
multiple
modalities
examine
hypotheses
spatial
temporal
scales,
experimental
utilising
large-scale
consortia
advance
biomarker
identification.
Translation
practice
will
aided
consideration
optimal
intervention
timings,
biomarker-led
patient
stratification,
selective
medications.
Biomolecules,
Год журнала:
2024,
Номер
14(8), С. 906 - 906
Опубликована: Июль 25, 2024
Schizophrenia
is
a
frequently
debilitating
and
complex
mental
disorder
affecting
approximately
1%
of
the
global
population,
characterized
by
symptoms
such
as
hallucinations,
delusions,
disorganized
thoughts
behaviors,
cognitive
dysfunction,
negative
symptoms.
Traditional
treatment
has
centered
on
postsynaptic
dopamine
antagonists,
commonly
known
antipsychotic
drugs,
which
aim
to
alleviate
improve
functioning
quality
life.
Despite
availability
these
medications,
significant
challenges
remain
in
schizophrenia
therapeutics,
including
incomplete
symptom
relief,
resistance,
medication
side
effects.
This
opinion
article
explores
advancements
treatment,
emphasizing
molecular
mechanisms,
novel
drug
targets,
innovative
delivery
methods.
One
promising
approach
strategies
that
target
neural
networks
circuits
rather
than
single
neurotransmitters,
acknowledging
complexity
brain
region
interconnections
involved
schizophrenia.
Another
development
biased
agonists,
selectively
activate
specific
signaling
pathways
downstream
receptors,
offering
potential
for
more
precise
pharmacological
interventions
with
fewer
The
concept
polypharmacy,
where
targets
multiple
pathways,
exemplified
KarXT,
combining
xanomeline
trospium
address
both
psychosis
dysfunction.
represents
comprehensive
strategy
potentially
improving
outcomes
patients.
In
conclusion,
advancing
understanding
exploring
therapeutic
hold
promise
addressing
unmet
needs
aiming
effective
tailored
interventions.
Future
research
should
focus
approaches
achieve
better
clinical
functional
level
life
individuals
Brain Sciences,
Год журнала:
2025,
Номер
15(2), С. 195 - 195
Опубликована: Фев. 14, 2025
Most
brain
development
occurs
in
the
"first
1000
days",
a
critical
period
from
conception
to
child's
second
birthday.
Critical
processes
that
occur
during
this
time
include
synaptogenesis,
myelination,
neural
pruning,
and
formation
of
functioning
neuronal
circuits.
Perturbations
first
days
likely
contribute
later-life
neurodegenerative
disease,
including
sporadic
amyotrophic
lateral
sclerosis
(ALS).
Neurodevelopment
is
determined
by
many
events,
maturation
colonization
infant
microbiome
its
metabolites,
specifically
neurotransmitters,
immune
modulators,
vitamins,
short-chain
fatty
acids.
Successful
gut-brain
axis
function
depend
on
maternal
factors
(stress
exposure
toxins
pregnancy),
mode
delivery,
quality
postnatal
environment,
diet
after
weaning
breast
milk,
nutritional
deficiencies.
While
neonatal
highly
plastic,
it
remains
prone
dysbiosis
which,
once
established,
may
persist
into
adulthood,
thereby
inducing
chronic
inflammation
abnormal
excitatory/inhibitory
balance,
resulting
excitation.
Both
are
recognized
as
key
pathophysiological
ALS.
Biology,
Год журнала:
2025,
Номер
14(4), С. 363 - 363
Опубликована: Март 31, 2025
The
excitation/inhibition
(E/I)
balance
is
a
critical
feature
of
neural
circuits,
which
crucial
for
maintaining
optimal
brain
function
by
ensuring
network
stability
and
preventing
hyperexcitability.
hippocampus
exhibits
the
particularly
interesting
characteristics
having
different
functions
E/I
profiles
between
its
dorsal
ventral
segments.
Furthermore,
vulnerable
to
epilepsy
implicated
in
Fragile
X
Syndrome
(FXS),
disorders
associated
with
heightened
possible
deficits
GABA-mediated
inhibition.
In
epilepsy,
shows
susceptibility
seizures,
while
FXS,
recent
evidence
suggests
differential
alterations
excitability
inhibition
regions.
This
article
explores
mechanisms
underlying
regulation,
focusing
on
emphasizing
that
may
confer
homeostatic
flexibility
balance.
Notably,
adult
FXS
models
enhanced
GABAergic
inhibition,
resistance
epileptiform
activity,
physiological
pattern
(sharp
wave-ripples,
SWRs),
potentially
representing
adaptation.
contrast,
these
more
aberrant
discharges
displays
altered
SWRs.
These
findings
highlight
complex,
region-specific
nature
disruptions
neurological
suggest
possess
unique
compensatory
mechanisms.
Specifically,
it
proposed
hippocampus,
region
most
prone
hyperexcitability,
have
adaptive
capabilities
at
cellular
levels
maintain
within
normal
range
prevent
transition
hyperexcitability
preserve
function.
Investigating
responses
their
developmental
trajectories
offer
novel
insights
into
strategies
mitigating
imbalances
other
neuropsychiatric
neurodevelopmental
disorders.
