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Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors.
[gm1 gangliosidosis]
The
insertion
and
removal
of
NMDA
receptors
from
the
synapse
are
critical
events
that
modulate
synaptic
plasticity
.
While
a
great
deal
of
progress
has
been
made
on
understanding
the
mechanisms
that
modulate
trafficking
of
NMDA
receptors
,
we
do
not
currently
understand
the
molecular
events
required
for
the
fusion
of
receptor
containing
vesicles
with
the
plasma
membrane
.
Here
,
we
show
that
sphingomyelin
phosphodiesterase
3
(
also
known
as
neutral
sphingomyelinase-
2
)
is
critical
for
tumor
necrosis
factor
(
TNF
)
alpha-induced
trafficking
of
NMDA
receptors
and
synaptic
plasticity
.
TNFalpha
initiated
a
rapid
increase
in
ceramide
that
was
associated
with
increased
surface
localization
of
NMDA
receptor
NR
1
subunits
and
a
specific
clustering
of
NR
1
phosphorylated
on
serines
896
and
897
into
lipid
rafts
.
Brief
applications
of
TNFalpha
increased
the
rate
and
amplitude
of
NMDA-evoked
calcium
bursts
and
enhanced
excitatory
post-synaptic
currents
.
Pharmacological
inhibition
or
genetic
mutation
of
neutral
sphingomyelinase-
2
prevented
TNFalpha-induced
generation
of
ceramide
,
phosphorylation
of
NR
1
subunits
,
clustering
of
NR
1
,
enhancement
of
NMDA-evoked
calcium
flux
and
excitatory
post-synaptic
currents
.
