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Impaired glutamatergic synaptic transmission in the PKU brain.
[classical phenylketonuria]
This
paper
reviews
recent
results
of
our
investigation
of
the
mechanisms
whereby
hyperphenylalaninemia
may
cause
brain
dysfunction
in
classical
phenylketonuria
(
PKU
)
.
Acute
applications
of
L-Phe
in
rat
and
mouse
hippocampal
and
cerebrocortical
cultured
neurons
,
at
a
range
of
concentrations
found
in
PKU
brain
,
significantly
and
reversibly
depressed
glutamatergic
synaptic
transmission
by
a
combination
of
pre-
and
postsynaptic
actions
:
(
1
)
competition
for
the
glycine-binding
site
of
the
N-
methyl-
D-
aspartate
(
NMDA
)
receptors
;
(
2
)
attenuation
of
neurotransmitter
release
;
(
3
)
competition
for
the
glutamate-binding
site
of
(
RS
)
-
amino-
3
-
hydroxy-
5
-
methyl-
4
-
isoxazolepropioinic
acid
and
kainate
(
AMPA
/
kainate
)
receptors
.
Unlike
L-Phe
,
its
non-tyrosine
metabolites
,
phenylacetic
acid
,
phenylpyruvic
acid
,
and
phenyllactic
acid
,
did
not
produce
antiglutamatergic
effects
.
L-Phe
did
not
affect
inhibitory
gamma-aminobutyric
(
GABA
)
-
ergic
transmission
.
Consistent
with
this
specific
pattern
of
effects
caused
by
L-Phe
in
neuronal
cultures
,
the
expression
of
NMDA
receptor
NR
2
A
and
AMPA
receptor
Glu
1
and
Glu
2
/
3
subunits
in
brain
of
hyperphenylalaninemic
PKU
mice
(
Pah
(
enu
2
)
strain
)
was
significantly
increased
,
whereas
expression
of
the
NMDA
receptor
NR
2
B
subunit
was
decreased
.
There
was
no
change
in
GABA
alpha
1
subunit
expression
.
Considering
the
important
role
of
glutamatergic
synaptic
transmission
in
normal
brain
development
and
function
,
these
L-Phe-induced
changes
in
glutamatergic
synaptic
transmission
in
PKU
brain
may
be
a
critical
element
of
the
neurological
symptoms
of
PKU
.
Diseases
Validation
Diseases presenting
"cerebrocortical cultured neurons"
symptom
classical phenylketonuria
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