Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(10), С. 5549 - 5549
Опубликована: Май 19, 2024
Parvalbumin
expressing
(PV+)
GABAergic
interneurons
are
fast
spiking
neurons
that
provide
powerful
but
relatively
short-lived
inhibition
to
principal
excitatory
cells
in
the
brain.
They
play
a
vital
role
feedforward
and
feedback
synaptic
inhibition,
preventing
run
away
excitation
neural
networks.
Hence,
their
dysfunction
can
lead
hyperexcitability
increased
susceptibility
seizures.
PV+
also
key
players
generating
gamma
oscillations,
which
synchronized
oscillations
associated
with
various
cognitive
functions.
interneuron
particularly
vulnerable
aging
degeneration
has
been
decline
memory
impairment
dementia
Alzheimer’s
disease
(AD).
Overall,
of
disrupts
normal
excitatory/inhibitory
balance
within
specific
neurocircuits
brain
thus
linked
wide
range
neurodevelopmental
neuropsychiatric
disorders.
This
review
focuses
on
dysfunctional
inhibitory
generation
epileptic
seizures
potential
as
targets
design
future
therapeutic
strategies
treat
these
Recent
research
using
cutting-edge
optogenetic
chemogenetic
technologies
demonstrated
they
be
selectively
manipulated
control
restore
activity
brains
animal
models.
suggests
could
important
developing
treatments
for
patients
epilepsy
comorbid
disorders,
such
AD,
where
directly
deficits.
Язык: Английский
A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(3)
Опубликована: Янв. 9, 2024
De
novo
heterozygous
variants
in
KCNC2
encoding
the
voltage-gated
potassium
(K
+
)
channel
subunit
Kv3.2
are
a
recently
described
cause
of
developmental
and
epileptic
encephalopathy
(DEE).
A
de
variant
c.374G
>
(p.Cys125Tyr)
was
identified
via
exome
sequencing
patient
with
DEE.
Relative
to
wild-type
Kv3.2,
Kv3.2-p.Cys125Tyr
induces
K
currents
exhibiting
large
hyperpolarizing
shift
voltage
dependence
activation,
accelerated
delayed
deactivation
consistent
relative
stabilization
open
conformation,
along
increased
current
density.
Leveraging
cryogenic
electron
microscopy
(cryo-EM)
structure
Kv3.1,
molecular
dynamic
simulations
suggest
that
strong
π-π
stacking
interaction
between
Tyr125
Tyr156
α-6
helix
T1
domain
promotes
conformation
channel,
which
underlies
observed
gain
function.
multicompartment
computational
model
Kv3-expressing
parvalbumin-positive
cerebral
cortex
fast-spiking
γ-aminobutyric
acidergic
(GABAergic)
interneuron
(PV-IN)
demonstrates
how
Kv3.2-Cys125Tyr
impairs
neuronal
excitability
dysregulates
inhibition
circuits
explain
resulting
epilepsy.
Язык: Английский
The binding and mechanism of a positive allosteric modulator of Kv3 channels
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Март 21, 2024
Abstract
Small-molecule
modulators
of
diverse
voltage-gated
K
+
(Kv)
channels
may
help
treat
a
wide
range
neurological
disorders.
However,
developing
effective
requires
understanding
their
mechanism
action.
We
apply
an
orthogonal
approach
to
elucidate
the
action
imidazolidinedione
derivative
(AUT5),
highly
selective
positive
allosteric
modulator
Kv3.1
and
Kv3.2
channels.
AUT5
modulation
involves
cooperativity
preferential
stabilization
open
state.
The
cryo-EM
structure
Kv3.1/AUT5
complex
at
resolution
2.5
Å
reveals
four
equivalent
binding
sites
extracellular
inter-subunit
interface
between
voltage-sensing
pore
domains
channel’s
tetrameric
assembly.
Furthermore,
we
show
that
unique
turret
regions
essentially
govern
by
AUT5.
High-resolution
apo
bound
structures
demonstrate
how
promotes
rearrangements
interactions
with
domain
favor
conformation.
Язык: Английский
Voltage-gated potassium channels as a potential therapeutic target for the treatment of neurological and psychiatric disorders
Frontiers in Cellular Neuroscience,
Год журнала:
2024,
Номер
18
Опубликована: Окт. 1, 2024
Voltage-gated
potassium
channels
are
a
widely
distributed
subgroup
of
responsible
for
the
efflux
in
repolarisation
cell
membrane,
and
hence
contribute
to
latency
propagation
action
potentials.
As
they
causal
synaptic
transmission,
alterations
structure
these
can
lead
variety
neurological
psychiatric
diseases.
The
Kv3
subfamily
voltage-gated
found
on
many
neurons
brain,
including
inhibitory
interneurons
where
fast-frequency
firing.
Changes
firing
ability
an
imbalance
excitatory
neurotransmission.
To
date,
we
have
little
understanding
mechanism
by
which
inputs
become
imbalanced.
This
is
associated
with
cognitive
deficits
seen
across
neuropsychiatric
disorders,
currently
difficult
treat.
In
this
review,
collate
evidence
supporting
hypothesis
that
channels,
specifically
subfamily,
central
may
thus
be
considered
as
effective
drug
target.
collective
provided
studies
reviewed
here
demonstrates
amenable
novel
treatments
modulate
activity
prospect
improved
patient
outcome.
Язык: Английский
Voltage-gated ion channels in epilepsies: circuit dysfunctions and treatments
Trends in Pharmacological Sciences,
Год журнала:
2024,
Номер
45(11), С. 1018 - 1032
Опубликована: Окт. 14, 2024
Язык: Английский
Mitigating sTNF/TNFR1 activation on VGluT2+ spinal cord interneurons improves immune function after mid-thoracic spinal cord injury
Опубликована: Июль 13, 2024
Abstract
Spinal
cord
injury
(SCI)
is
a
devastating
condition
with
250,000
to
500,000
new
cases
globally
each
year.
Respiratory
infections,
e.g.,
pneumonia
and
influenza
are
the
leading
cause
of
death
after
SCI.
Unfortunately,
there
poor
understanding
how
altered
neuro-immune
communication
impacts
an
individual’s
outcome
infection.
In
humans
rodents,
SCI
leads
maladaptive
changes
in
spinal-sympathetic
reflex
(SSR)
circuit
which
crucial
sympathetic
function.
The
impaired
immune
function
may
be
related
harmful
neuroinflammation
detrimental
homeostatic
neuronal
function,
aberrant
plasticity,
hyperexcitable
circuits.
Soluble
tumor
necrosis
factor
(sTNF)
pro-inflammatory
cytokine
that
elevated
CNS
remains
for
several
months
injury.
By
pharmacologically
attenuating
sTNF
we
were
able
demonstrate
improved
Furthermore,
when
investigated
specific
cellular
population
involved
reported
excessive
TNFR1
activity
on
excitatory
INs
promotes
dysfunction.
this
observation
NF-kB
dependent
VGluT2+
INs.
Our
data
first
report
target
within
CNS,
TNFR1,
contributes
SCI-induced
dysfunction
T9-SCI
potential
avenue
future
therapeutics.
Язык: Английский
Impaired excitability of fast-spiking neurons in a novel mouse model ofKCNC1epileptic encephalopathy
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 27, 2024
The
recurrent
pathogenic
variant
Язык: Английский
Mitigating sTNF/TNFR1 activation on VGluT2 + spinal cord interneurons improves immune function after mid-thoracic spinal cord injury
Brain Behavior and Immunity,
Год журнала:
2024,
Номер
123, С. 633 - 643
Опубликована: Окт. 15, 2024
Язык: Английский
Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy
Опубликована: Дек. 2, 2024
The
recurrent
pathogenic
variant
KCNC1
-p.Ala421Val
(A421V)
is
a
cause
of
developmental
and
epileptic
encephalopathy
characterized
by
moderate-to-severe
delay/intellectual
disability,
infantile-onset
treatment-resistant
epilepsy
with
multiple
seizure
types
including
myoclonic
seizures.
Yet,
the
mechanistic
basis
disease
unclear.
encodes
Kv3.1,
voltage-gated
potassium
channel
subunit
that
highly
selectively
expressed
in
neurons
capable
generating
action
potentials
at
high
frequency,
parvalbumin-positive
fast-spiking
GABAergic
inhibitory
interneurons
cerebral
cortex
(PV-INs)
known
to
be
important
for
cognitive
function
plasticity
as
well
control
network
excitation
prevent
In
this
study,
we
generate
novel
transgenic
mouse
model
conditional
expression
Ala421Val
missense
(
Kcnc1
-A421V/+
mice)
explore
physiological
mechanisms
encephalopathy.
Our
results
indicate
global
heterozygous
A421V
leads
premature
lethality.
We
observe
decreased
PV-IN
cell
surface
Kv3.1
via
immunohistochemistry,
current
density
PV-INs
using
outside-out
nucleated
macropatch
recordings
brain
slice,
profound
impairments
intrinsic
excitability
but
not
excitatory
current-clamp
electrophysiology.
vivo
two-photon
calcium
imaging
revealed
hypersynchronous
discharges
correlated
brief
paroxysmal
movements,
subsequently
shown
seizures
on
electroencephalography.
found
alterations
PV-IN-mediated
neurotransmission
young
adult
juvenile
mice
relative
wild-type
controls.
Together,
these
establish
impact
Kv3.1-A421V
neuronal
synaptic
physiology
across
development
drive
dysfunction
underlying
Язык: Английский
Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy
Опубликована: Дек. 2, 2024
The
recurrent
pathogenic
variant
KCNC1
-p.Ala421Val
(A421V)
is
a
cause
of
developmental
and
epileptic
encephalopathy
characterized
by
moderate-to-severe
delay/intellectual
disability,
infantile-onset
treatment-resistant
epilepsy
with
multiple
seizure
types
including
myoclonic
seizures.
Yet,
the
mechanistic
basis
disease
unclear.
encodes
Kv3.1,
voltage-gated
potassium
channel
subunit
that
highly
selectively
expressed
in
neurons
capable
generating
action
potentials
at
high
frequency,
parvalbumin-positive
fast-spiking
GABAergic
inhibitory
interneurons
cerebral
cortex
(PV-INs)
known
to
be
important
for
cognitive
function
plasticity
as
well
control
network
excitation
prevent
In
this
study,
we
generate
novel
transgenic
mouse
model
conditional
expression
Ala421Val
missense
(
Kcnc1
-A421V/+
mice)
explore
physiological
mechanisms
encephalopathy.
Our
results
indicate
global
heterozygous
A421V
leads
premature
lethality.
We
observe
decreased
PV-IN
cell
surface
Kv3.1
via
immunohistochemistry,
current
density
PV-INs
using
outside-out
nucleated
macropatch
recordings
brain
slice,
profound
impairments
intrinsic
excitability
but
not
excitatory
current-clamp
electrophysiology.
vivo
two-photon
calcium
imaging
revealed
hypersynchronous
discharges
correlated
brief
paroxysmal
movements,
subsequently
shown
seizures
on
electroencephalography.
found
alterations
PV-IN-mediated
neurotransmission
young
adult
juvenile
mice
relative
wild-type
controls.
Together,
these
establish
impact
Kv3.1-A421V
neuronal
synaptic
physiology
across
development
drive
dysfunction
underlying
Язык: Английский