SYNGAP1
haploinsufficiency-related
intellectual
disability
(SYNGAP1-ID)
is
characterized
by
moderate
to
severe
ID,
generalized
epilepsy,
autism
spectrum
disorder,
sensory
processing
dysfunction
and
other
behavioral
abnormalities.
While
numerous
studies
have
highlighted
a
role
of
Syngap1
in
cortical
excitatory
neurons
development;
recent
suggest
that
plays
GABAergic
inhibitory
neuron
development
as
well.
However,
the
molecular
pathways
which
acts
on
neurons,
whether
they
are
similar
or
different
from
mechanisms
underlying
its
effects
unknown.
Here,
we
examined
whether,
how,
embryonic-onset
haploinsufficiency
restricted
interneurons
derived
medial
ganglionic
eminence
(MGE)
impacts
their
synaptic
intrinsic
properties
adult
primary
auditory
cortex
(A1).
We
found
affects
properties,
overall
leading
increased
firing
threshold,
decreased
drive
Parvalbumin
(PV)+
Layer
IV
A1,
whilst
Somatostatin
(SST)+
were
mostly
resistant
haploinsufficiency.
Further,
AMPA
component
thalamocortical
evoked-EPSC
was
PV+
cells
mutant
mice.
Finally,
selective
blocking
voltage-gated
D-type
K+
currents
sufficient
rescue
cell-intrinsic
wild-type
levels.
Together,
these
data
specific
maturation
cell
drive,
may
lead
reduced
PV
recruitment
could
turn
contribute
alterations
SYNGAP1-ID
preclinical
models
patients.
Neuron,
Journal Year:
2024,
Volume and Issue:
112(21), P. 3602 - 3617.e9
Published: Oct. 14, 2024
Human-specific
(HS)
genes
have
been
implicated
in
brain
evolution,
but
their
impact
on
human
neuron
development
and
diseases
remains
unclear.
Here,
we
study
SRGAP2B/C,
two
HS
gene
duplications
of
the
ancestral
synaptic
SRGAP2A,
cortical
pyramidal
neurons
(CPNs)
xenotransplanted
mouse
cortex.
Downregulation
SRGAP2B/C
CPNs
led
to
strongly
accelerated
development,
indicating
requirement
for
neoteny
that
distinguishes
synaptogenesis.
promoted
by
reducing
levels
SRGAP2A,thereby
increasing
postsynaptic
accumulation
SYNGAP1
protein,
encoded
a
major
intellectual
disability/autism
spectrum
disorder
(ID/ASD)
gene.
Combinatorial
loss-of-function
experiments
vivo
revealed
tempo
synaptogenesis
is
set
reciprocal
antagonism
between
SRGAP2A
SYNGAP1,
which
tipped
toward
SRGAP2B/C.
Thus,
can
modify
phenotypic
expression
genetic
mutations
leading
ID/ASD
through
regulation
neoteny.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 13, 2025
Traditional
phenotypic
drug
discovery
platforms
have
suffered
from
poor
scalability
and
a
lack
of
mechanistic
understanding
newly
discovered
probes.
To
address
this,
we
created
Endo-
GeneScreen
(EGS),
high-throughput
enabled
screening
platform
that
identifies
bioactive
small
molecules
capable
regulating
endogenous
protein
expression
encoded
by
any
preselected
target
gene
within
biologically
appropriate
context.
As
proof-of-concept,
EGS
successfully
identified
candidates
up-regulate
neuronal
Syngap1,
causes
neurodevelopmental
disorder
when
haploinsufficient.
For
example,
SR-1815,
previously
unknown
undescribed
kinase
inhibitor,
alleviated
major
cellular
consequences
Syngap1
loss-of-function
restoring
normal
SynGAP
levels
dampening
hyperactivity
haploinsufficient
neurons.
Moreover,
demonstrate
assays
accelerate
preclinical
development
facilitate
mode-of-action
deconvolution
studies.
Thus,
first-in-class
molecule
probes
promote
biological
precision
therapeutic
development.
Current Opinion in Neurobiology,
Journal Year:
2025,
Volume and Issue:
92, P. 103018 - 103018
Published: April 11, 2025
The
field
of
brain
organoids
has
experienced
a
period
rapid
and
transformative
growth,
enabling
researchers
to
investigate
complex
human
biological
mechanisms
that
were
previously
deemed
intractable.
This
review
provides
an
overview
the
current
landscape
organoids,
with
particular
focus
on
their
relevance
in
context
neurodevelopmental
disorders.
It
also
emphasizes
crucial
role
these
models
play
elucidating
both
cell-autonomous
non-cell-autonomous
mechanisms.
We
describe
how
two
mechanisms,
often
considered
be
independent,
are
intricately
interconnected.
In
conclusion,
this
aims
highlight
utilization
considerably
advanced
our
comprehension
disorders,
while
delineating
prospective
avenues
for
investigating
conditions.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Aug. 24, 2024
Over
a
hundred
risk
genes
underlie
for
autism
spectrum
disorder
(ASD)
but
the
extent
to
which
they
converge
on
shared
downstream
targets
increase
ASD
is
unknown.
To
test
hypothesis
that
cellular
context
impacts
nature
of
convergence,
here
we
apply
pooled
CRISPR
approach
target
29
loss-of-function
in
human
induced
pluripotent
stem
cell
(hiPSC)-derived
neural
progenitor
cells,
glutamatergic
neurons,
and
GABAergic
neurons.
Two
distinct
approaches
(gene-level
network-level
analyses)
demonstrate
convergence
greatest
mature
Convergent
effects
are
dynamic,
varying
strength,
composition,
biological
role
between
types,
increasing
with
functional
similarity
examined,
driven
by
cell-type-specific
gene
co-expression
patterns.
Stratification
yield
targeted
drug
predictions
capable
reversing
gene-specific
convergent
signatures
cells
ASD-related
behaviors
zebrafish.
Altogether,
networks
represent
novel
points
individualized
therapeutic
intervention.
SYNGAP1
haploinsufficiency-related
intellectual
disability
(SYNGAP1-ID)
is
characterized
by
moderate
to
severe
ID,
generalized
epilepsy,
autism
spectrum
disorder,
sensory
processing
dysfunction
and
other
behavioral
abnormalities.
While
numerous
studies
have
highlighted
a
role
of
Syngap1
in
cortical
excitatory
neurons
development;
recent
suggest
that
plays
GABAergic
inhibitory
neuron
development
as
well.
However,
the
molecular
pathways
which
acts
on
neurons,
whether
they
are
similar
or
different
from
mechanisms
underlying
its
effects
unknown.
Here,
we
examined
whether,
how,
embryonic-onset
haploinsufficiency
restricted
interneurons
derived
medial
ganglionic
eminence
(MGE)
impacts
their
synaptic
intrinsic
properties
adult
primary
auditory
cortex
(A1).
We
found
affects
properties,
overall
leading
increased
firing
threshold,
decreased
drive
Parvalbumin
(PV)+
Layer
IV
A1,
whilst
Somatostatin
(SST)+
were
mostly
resistant
haploinsufficiency.
Further,
AMPA
component
thalamocortical
evoked-EPSC
was
PV+
cells
mutant
mice.
Finally,
selective
blocking
voltage-gated
D-type
K+
currents
sufficient
rescue
cell-intrinsic
wild-type
levels.
Together,
these
data
specific
maturation
cell
drive,
may
lead
reduced
PV
recruitment
could
turn
contribute
alterations
SYNGAP1-ID
preclinical
models
patients.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Feb. 29, 2024
Abstract
SYNGAP1
haploinsufficiency-related
intellectual
disability
(SYNGAP1-ID)
is
characterized
by
moderate
to
severe
ID,
generalized
epilepsy,
autism
spectrum
disorder,
sensory
processing
dysfunction
and
other
behavioral
abnormalities.
While
numerous
studies
have
highlighted
a
role
of
Syngap1
in
cortical
excitatory
neurons
development;
recent
suggest
that
plays
GABAergic
inhibitory
neuron
development
as
well.
However,
the
molecular
pathways
which
acts
on
neurons,
whether
they
are
similar
or
different
from
mechanisms
underlying
its
effects
unknown.
Here,
we
examined
whether,
how,
embryonic-onset
haploinsufficiency
restricted
interneurons
derived
medial
ganglionic
eminence
(MGE)
impacts
their
synaptic
intrinsic
properties
adult
primary
auditory
cortex
(A1).
We
found
affects
properties,
overall
leading
increased
firing
threshold,
decreased
drive
Parvalbumin
(PV)+
Layer
IV
A1,
whilst
Somatostatin
(SST)+
were
mostly
resistant
haploinsufficiency.
Further,
AMPA
component
thalamocortical
evoked-EPSC
was
PV+
cells
mutant
mice.
Finally,
selective
blocking
voltage-gated
D-type
K+
currents
sufficient
rescue
cell-intrinsic
wild-type
levels.
Together,
these
data
specific
maturation
cell
drive,
may
lead
reduced
PV
recruitment
could
turn
contribute
alterations
SYNGAP1-ID
preclinical
models
patients.
