Frontiers in Molecular Neuroscience,
Год журнала:
2022,
Номер
14
Опубликована: Янв. 6, 2022
Fragile
X
Syndrome
(FXS)
is
a
leading
inherited
cause
of
autism
and
intellectual
disability,
resulting
from
mutation
in
the
FMR1
gene
subsequent
loss
its
protein
product
FMRP.
Despite
this
simple
genetic
origin,
FXS
phenotypically
complex
disorder
with
range
physical
neurocognitive
disruptions.
While
numerous
molecular
cellular
pathways
are
affected
by
FMRP
loss,
there
growing
evidence
that
circuit
hyperexcitability
may
be
common
convergence
point
can
account
for
many
wide-ranging
phenotypes
seen
FXS.
The
mechanisms
include
alterations
to
excitatory
synaptic
function
connectivity,
reduced
inhibitory
neuron
activity,
as
well
changes
ion
channel
expression
conductance.
However,
understanding
impact
on
complicated
inherent
plasticity
neural
circuits,
which
display
an
array
homeostatic
maintain
activity
near
set
levels.
also
important
regulator
activity-dependent
brain,
meaning
dysregulated
both
consequence
hyperexcitable
networks
This
makes
it
difficult
separate
direct
effects
myriad
pleiotropic
compensatory
associated
it,
likely
contribute
pathophysiology.
Here
we
will:
(1)
review
models,
focusing
similarities/differences
across
brain
regions,
cell-types,
developmental
time
points;
(2)
examine
how
excitability
disruptions
interact
each
other
ultimately
dysfunction
FXS;
(3)
discuss
these
deficits
disease-relevant
behavioral
like
epilepsy
sensory
hypersensitivity.
Through
discussion
where
current
field
stands,
aim
introduce
perspectives
moving
forward
research.
Journal of Genetic Engineering and Biotechnology,
Год журнала:
2021,
Номер
19(1), С. 123 - 123
Опубликована: Авг. 21, 2021
γ-Aminobutyric
acid
sub-type
A
receptors
(GABAARs)
are
the
most
prominent
inhibitory
neurotransmitter
in
CNS.
They
a
family
of
ligand-gated
ion
channel
with
significant
physiological
and
therapeutic
implications.GABAARs
heteropentamers
formed
from
selection
19
subunits:
six
α
(alpha1-6),
three
β
(beta1-3),
γ
(gamma1-3),
ρ
(rho1-3),
one
each
δ
(delta),
ε
(epsilon),
π
(pi),
θ
(theta)
which
result
production
considerable
number
receptor
isoforms.
Each
isoform
exhibits
distinct
pharmacological
properties.
However,
majority
GABAARs
composed
two
subunits,
subunit
arranged
as
γ2β2α1β2α1
counterclockwise
around
center.
The
mature
has
central
chloride
gated
by
GABA
modulated
variety
different
drugs.
Changes
synthesis
or
release
may
have
effect
on
normal
brain
function.
Furthermore,
molecular
interactions
effects
caused
drugs
extremely
complex.
This
is
due
to
structural
heterogeneity
receptors,
existence
multiple
allosteric
binding
sites
well
wide
range
ligands
that
can
bind
them.
Notably,
dysfunction
GABAergic
system
contributes
development
several
diseases.
Therefore,
understanding
relationship
between
GABAA
deficits
CNS
disorders
thus
impact
discovery
disease
pathogenesis
drug
development.To
date,
few
reviews
discussed
detail.
Accordingly,
this
review
aims
summarize
current
structural,
physiological,
properties
GABAARs,
shedding
light
common
associated
disorders.
Frontiers in Aging Neuroscience,
Год журнала:
2019,
Номер
11
Опубликована: Июнь 24, 2019
Since
first
described
in
the
early
1900s,
Alzheimer's
disease
(AD)
has
risen
exponentially
prevalence
and
concern.
Research
still
drives
to
understand
etiology
pathogenesis
of
this
what
risk
factors
can
attribute
AD.
With
a
majority
AD
cases
being
sporadic
origin,
increasing
exponential
growth
an
aged
population
lack
treatment,
it
is
imperative
discover
easy
accessible
preventative
method
for
Some
increase
propensity
such
as
aging,
sex,
genetics.
Moreover,
there
are
also
modifiable
factors-in
terms
treatable
medical
conditions
lifestyle
choices-that
play
role
developing
These
have
their
own
biological
mechanisms
that
may
contribute
pathological
consequences.
In
review
article,
we
will
discuss
current
literature
how
each
these
interplay
into
development
progression
if
strategically
analyzed
treated,
could
aid
protection
against
neurodegenerative
disease.
Molecular Psychiatry,
Год журнала:
2019,
Номер
25(12), С. 3380 - 3398
Опубликована: Авг. 20, 2019
Abstract
Neuronal
network
dysfunction
is
increasingly
recognized
as
an
early
symptom
in
Alzheimer’s
disease
(AD)
and
may
provide
new
entry
points
for
diagnosis
intervention.
Here,
we
show
that
amyloid-beta-induced
hyperexcitability
of
hippocampal
inhibitory
parvalbumin
(PV)
interneurons
importantly
contributes
to
neuronal
memory
impairment
APP/PS1
mice,
a
mouse
model
increased
amyloidosis.
We
demonstrate
PV
become
hyperexcitable
at
~16
weeks
age,
when
no
changes
are
observed
yet
the
intrinsic
properties
pyramidal
cells.
This
state
coincides
with
transmission
onto
neurons
deficits
spatial
learning
memory.
treatment
aimed
preventing
from
becoming
sufficient
restore
interneuron
wild-type
levels,
reduce
input
cells,
rescue
mice.
Importantly,
intervention
restoring
activity
has
long-term
beneficial
effects
on
activity,
reduces
amyloid
plaque
deposition,
hallmark
AD
pathology.
Taken
together,
these
findings
suggest
hyperactivity
might
be
clinically
relevant
decline
delaying
progression.
Nature Communications,
Год журнала:
2019,
Номер
10(1)
Опубликована: Янв. 28, 2019
Abstract
Alzheimer’s
disease
(AD)
is
a
heterogeneous
disorder
with
multiple
etiologies.
Harnessing
the
immune
system
by
blocking
programmed
cell
death
receptor
(PD)-1
pathway
in
an
amyloid
beta
mouse
model
was
shown
to
evoke
sequence
of
responses
that
lead
modification.
Here,
PD-L1,
PD-1
ligand,
found
have
similar
efficacy
modification,
both
animal
models
AD
and
tauopathy.
Targeting
PD-L1
tau-driven
resulted
increased
immunomodulatory
monocyte-derived
macrophages
within
brain
parenchyma.
Single
RNA-seq
revealed
homing
expressed
unique
scavenger
molecules
including
macrophage
1
(MSR1),
which
here
be
required
for
effect
blockade
Overall,
our
results
demonstrate
checkpoint
targeting
PD-1/PD-L1
leads
modification
common
factors
go
awry
dementia,
thus
can
potentially
provide
immunotherapy
help
combat
these
diseases.
Frontiers in Neuroscience,
Год журнала:
2020,
Номер
14
Опубликована: Июнь 30, 2020
Alzheimer's
disease
(AD)
is
a
neurodegenerative
disorder
characterized
clinically
by
severe
cognitive
deficits
and
pathologically
amyloid
plaques,
neuronal
loss,
neurofibrillary
tangles.
Abnormal
β-protein
(Aβ)
deposition
in
the
brain
often
thought
of
as
major
initiating
factor
AD
neuropathology.
However,
gamma-aminobutyric
acid
(GABA)
inhibitory
interneurons
are
resistant
to
Aβ
deposition,
decreases
synaptic
glutamatergic
transmission
decrease
neural
network
activity.
Furthermore,
there
now
evidence
suggesting
that
activity
aberrantly
increased
patients
animal
models
due
functional
decreased
GABA
interneurons,
contributing
deficits.
Here
we
describe
roles
played
excitatory
neurons
Aβ-induced
how
altered
regulate
We
also
comprehensively
review
recent
studies
on
receptors
can
be
exploited
for
therapeutic
benefit.
an
emerging
target
AD,
with
further
clinical
trials
urgently
warranted.
Cells,
Год журнала:
2021,
Номер
10(3), С. 540 - 540
Опубликована: Март 4, 2021
Astrocytes
perform
a
wide
variety
of
essential
functions
defining
normal
operation
the
nervous
system
and
are
active
contributors
to
pathogenesis
neurodegenerative
disorders
such
as
Alzheimer’s
among
others.
Recent
data
provide
compelling
evidence
that
distinct
astrocyte
states
associated
with
specific
stages
Alzheimer´s
disease.
The
advent
transcriptomics
technologies
enables
rapid
progress
in
characterisation
pathological
states.
In
this
review,
we
an
overview
origin,
main
functions,
molecular
morphological
features
astrocytes
physiological
well
conditions
related
We
will
also
explore
roles
disease
summarize
transcriptional
changes
altered
pathways
observed
during
course