bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Май 14, 2025
Biallelic
pathogenic
variants
in
STRADA
,
an
upstream
regulator
of
the
mechanistic
target
rapamycin
(mTOR)
pathway,
result
megalencephaly,
drug-resistant
epilepsy,
and
severe
intellectual
disability.
This
study
explores
how
mTOR
pathway
hyperactivity
alters
cell
fate
specification
dorsal
ventral
forebrain
development
using
knock-out
human
stem
derived
brain
organoids.
In
both
organoids,
neurogenesis
is
delayed,
with
a
predilection
for
progenitor
renewal
proliferation
increase
outer
radial
glia.
Ventrally,
interneuron
subtypes
shift
to
neuropeptide-Y
expressing
cells.
Inhibition
results
rescue
most
phenotypes.
When
are
present
all
cells
developing
brain,
overproduction
interneurons
altered
may
underlie
mechanisms
cognitive
impairment.
Our
findings
suggest
inhibition
during
fetal
as
potential
therapeutic
strategy
deficiency.
The
identification
and
intervention
of
Alzheimer's
Disease
(AD)
in
its
early-stage
allows
for
the
timely
implementation
lifestyle
modifications
therapeutic
strategies.
Although
dysregulation
protein
expression
has
been
reported
brain
from
AD
patients
animal
models,
underlying
mechanisms
remain
poorly
understood.
N4-acetylcytidine
(ac4C),
only
known
form
RNA
acetylation
eukaryotes,
recently
shown
to
regulate
mRNA
stability
translation
efficiency.
However,
ac4C
associated
with
abnormal
levels
mouse
models
remains
be
elucidated.
This
study
investigated
modifications,
hippocampus
3
6-month-old
5×FAD
mice,
a
model
AD,
wild-type
(WT)
littermates.
multi-omics
analysis
was
performed:
acetylated
immunoprecipitation
followed
by
next-generation
sequencing
(acRIP-seq)
identify
mRNAs,
deep
(RNA-seq)
quantify
abundance,
label-free
quantitative
proteomics
assess
levels.
In
addition,
we
used
acRIP-qPCR,
regular
qPCR
western
blots
verify
ac4C,
some
key
genes
that
were
identified
high-throughput
assays.
Proteomic
revealed
significant
change
3-months-old
compared
WT
contrast,
RNA-seq
indicated
there
no
substantial
alterations
Strikingly,
acRIP-seq
notable
variations
modification
on
particularly
those
synaptic
structure
function,
found
correlated
changes.
Genes
are
essential
function
cognition,
including
GRIN1,
MAP2,
DNAJC6,
exhibited
reduced
without
any
corresponding
changes
levels,
Moreover,
small
part
dysregulated
mRNAs
3-month-old
mice
mice.
Altogether
these
results
may
contribute
synthesis
an
AD.
Neuronal
activity
must
be
regulated
in
a
narrow
permissive
band
for
the
proper
operation
of
neural
networks.
Changes
synaptic
connectivity
and
network
activity-for
example,
during
learning-might
disturb
this
balance,
eliciting
compensatory
mechanisms
to
maintain
function1-3.
In
neocortex,
excitatory
pyramidal
cells
inhibitory
interneurons
exhibit
robust
forms
stabilizing
plasticity.
However,
although
neuronal
plasticity
has
been
thoroughly
studied
cells4-8,
little
is
known
about
how
adapt
persistent
changes
their
activity.
Here
we
describe
critical
cellular
process
through
which
cortical
parvalbumin-expressing
(PV+)
levels.
We
found
that
individual
PV+
drive
bidirectional
adjustments
number
strength
synapses
received
by
these
cells,
specifically
from
other
interneurons.
High-throughput
profiling
ribosome-associated
mRNA
revealed
increasing
interneuron
leads
upregulation
two
genes
encoding
multiple
secreted
neuropeptides:
Vgf
Scg2.
Functional
experiments
demonstrated
VGF
critically
required
activity-dependent
scaling
onto
Our
findings
reveal
an
instructive
role
neuropeptide-encoding
regulating
connections
among
adult
mouse
neocortex.
The Journal of Physiology,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 11, 2025
Abstract
MicroRNAs
are
small,
highly
conserved
non‐coding
RNAs
that
negatively
regulate
mRNA
translation
and
stability.
In
the
brain,
miRNAs
contribute
to
neuronal
development,
synaptogenesis,
synaptic
plasticity.
MicroRNA
138‐5p
(miR‐138‐5p)
controls
inhibitory
transmission
in
hippocampus
is
expressed
cerebellar
excitatory
neurons.
However,
its
specific
role
remains
unknown.
Here,
we
investigated
cerebellum
of
mice
expressing
a
sponge
construct
sequesters
endogenous
miR‐138‐5p.
Mossy
fibre
stimulation‐evoked
EPSCs
granule
cells
were
∼40%
larger
miR‐138‐5p
compared
controls.
Furthermore,
observed
miniature
EPSC
amplitudes,
suggesting
an
increased
number
functional
postsynaptic
AMPA
receptors.
High‐frequency
train
stimulation
revealed
enhanced
short‐term
depression
following
downregulation.
Together
with
computational
modelling,
this
suggests
negative
regulation
presynaptic
release
probability.
Overall,
our
results
demonstrate
suppresses
strength
through
pre‐
mechanisms,
providing
potentially
powerful
mechanism
for
tuning
input
into
cerebellum.
image
Key
points
regulators
control
key
cell
biological
processes
including
transmission,
but
their
regulating
function
has
remained
elusive.
study,
how
microRNA‐138‐5p
modulates
at
adult
murine
mossy
synapses.
Downregulation
enhances
layer
increases
depression.
exerts
regulatory
both
mechanisms
by
probability
boutons,
as
well
receptor
numbers
cells.
These
findings
provide
insights
expand
understanding
microRNA‐dependent
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Май 14, 2025
Biallelic
pathogenic
variants
in
STRADA
,
an
upstream
regulator
of
the
mechanistic
target
rapamycin
(mTOR)
pathway,
result
megalencephaly,
drug-resistant
epilepsy,
and
severe
intellectual
disability.
This
study
explores
how
mTOR
pathway
hyperactivity
alters
cell
fate
specification
dorsal
ventral
forebrain
development
using
knock-out
human
stem
derived
brain
organoids.
In
both
organoids,
neurogenesis
is
delayed,
with
a
predilection
for
progenitor
renewal
proliferation
increase
outer
radial
glia.
Ventrally,
interneuron
subtypes
shift
to
neuropeptide-Y
expressing
cells.
Inhibition
results
rescue
most
phenotypes.
When
are
present
all
cells
developing
brain,
overproduction
interneurons
altered
may
underlie
mechanisms
cognitive
impairment.
Our
findings
suggest
inhibition
during
fetal
as
potential
therapeutic
strategy
deficiency.
