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Pharmacological Institute, College of Medicine (W.-L.C., C-M.T., W.-M.F.) and Department of Psychology (K.-C.L.), National Taiwan University; Taipei, Taiwan; Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan (S.-C.K., F.-Y.L.)
Received September 30, 2002; accepted February 19, 2002
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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; Schafe et al.,
2001). Schaffer collateral inputs to pyramidal neurons in the
hippocampus CA1 region exhibit a form of LTP that critically depends on
N-methyl-D-aspartate (NMDA) receptor-mediated
Ca2+ influx into the postsynaptic cell
(Tsien et al., 1996). It has
been suggested that nitric oxide (NO), generated postsynaptically by
Ca2+-calmodulin-dependent NO synthase (NOS), acts as a
retrograde messenger (Son et al.,
1996; Wilson et al.,
1997). A major target of NO is soluble guanylyl cyclase (sGC),
which generates the intracellular second messenger cGMP. Consistent with a
functional role of cGMP in the expression of LTP, sGC inhibitors suppress LTP
(Zhuo et al., 1994), and
membrane-permeable dibutyryl-cGMP partially reverses reduction of LTP by an
NOS inhibitor (Haley et al.,
1992). It is well known that GMP regulates the activity of diverse
proteins, including cGMP-dependent protein kinase (PKG). The critical role of
PKG was suggested by the finding that PKG inhibitors block LTP, and PKG
activators facilitate LTP in response to rather weak tetanic stimuli
(Zhuo et al., 1994).
A novel synthetic compound, YC-1, has been shown to activate purified sGC
and sensitize the enzyme for NO in vitro, in human platelets, and in smooth
muscle cells (Ko et al., 1994;
Mulsch et al., 1997;
Friebe et al., 1998). In the
presence of YC-1, NO produced an enormous stimulation of the sensitivity of
the purified enzyme to NO up to several hundredfold
(Friebe et al., 1996). We here
found that YC-1 enhanced LTP in hippocampal Schaffer collateral-CA1 synapse
via NO-cGMP-PKG-dependent pathway. In addition, YC-1 potentiated LTP induction
in amygdala as well. These findings suggest a therapeutic potential for YC-1
as a drug for improving learning and memory.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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, filled with 2 M NaCl solution). The pulse duration was
100 µs, and test responses were elicited at 0.02 Hz. The perfusion rate of
ACSF was 1 to 2 ml/min. To record field potentials in the cortico-amygdala
pathway, we placed the stimulating electrode in the external capsule, which
contained fibers from the auditory cortex to the lateral amygdala. Bicuculine
(10 µM) was present in the perfusion solution when the fEPSPs of amygdala
were recorded. All drugs were perfused in ACSF. Immunocytochemistry. Hippocampal slices were prepared and treated with drugs for 15 min. After the treatment, the slices were rapidly immersed in ice-cold 4% paraformaldehyde in PBS, pH 7.4, and fixed for 60 min. The slices were then washed three times in PBS, permeabilized in 0.3% Triton X-100 in PBS for 60 min at room temperature, and then washed three times in PBS again. Nonspecific antibody binding was blocked by incubation in 10% goat serum in PBS for 60 min at room temperature. The slices were then incubated with primary antibody, rabbit polyclonal anti-phospho-cAMP response element-binding protein (CREB; Upstate Biotechnology, Lake Placid, NY) or mouse anti-phospho-extracellular signal-regulated kinase (ERK; Santa Cruz Biotechnology, Santa Cruz, CA), diluted 1:100 in 10% bovine serum albumin in PBS at 4°C for 36 h. The slices were then washed repetitively in PBS and then incubated in fluorescein isothiocyanate-conjugated goat anti-rabbit (Leinco Technologies, Inc., Ballwin, MO) or goat anti-mouse (Jackson ImmuoResearch Laboratories, Inc., West Grove, PA) antibodies diluted 1:100 in PBS at 4°C. They were then washed again in PBS. The slices were viewed using a Zeiss Axioskop2 microscope (Zeiss, Welwyn Garden City, UK). The specificity of the immunofluorescence was confirmed by omitting the primary antibody, which resulted in a significant reduction in fluorescence intensity.
Western Blotting Analysis. Floating unstimulated hippocampal slices were incubated with ACSF and bubbled with 95% O2/5% CO2. The hippocampal slices were treated with drugs for 15 min. After the drug treatment, the slices were homogenized immediately in ice-cold buffer A (50 mM Tris-HCl, pH 7.4, 1 mM EGTA, 1 mM EDTA, 10 µM benzamidine, 1 µg/ml aprotinin, 1 µg/ml leupeptin, 2 mM sodium pyrophosphate, 4 mM p-nitrophenylphosphate, and 1 mM sodium orthovanadate) and centrifuged at 14,000g at 4°C for 30 min. The supernatant was decanted, saved, and used as soluble fraction for the detection of pERK.
For preparation of nuclear extracts, the tissue samples were disrupted with
a dounce homogenizer in ice-cold buffer B (0.25 M sucrose, 100 mM KCl, 10 mM
NaCl, 1 mM EGTA, 5 mM EDTA, 50 mM NaF, 1 mM sodium orthovanadate, 1 mM PMSF,
10 µM benzamidine, 10 µg/ml leupeptin, and 10 µg/ml aprotinin, pH
7.2) and incubated on ice for 10 min and then centrifuged at 2,000g
at 4°C for 15 min. The supernatant was thrown away, and the pellet was
placed in ice-cold buffer C (10 mM HEPES, 1.5 mM MgCl2, 10 mM KCl,
50 mM NaF, 1 mM sodium orthovanadate, 1 mM PMSF, 10 µg/ml leupeptin, and 10
µg/ml aprotinin, pH 7.2) on ice for 5 min and then homogenized carefully
(
10–15 strokes) and centrifuged at 4,000g at 4°C for
15 min. The nuclear pellet was resuspended in 30 µl of buffer D (10 mM
HEPES, 1.5 mM MgCl2, 1 mM EDTA, 0.8 M NaCl, 25% glycerol, 50 mM
NaF, 1 mM sodium orthovanadate, 1 mM PMSF, 10 µg/ml leupeptin, and 10
µg/ml aprotinin, pH 7.0) and incubated for overnight at 4°C, followed
by centrifugation at 14,000g at 4°C for 15 min. The resulting
supernatant was decanted, saved, and used as nuclear extract.
Equivalent amounts of protein for each sample were resolved by 12% SDS gel, blotted electrophoretically to Immobilon membranes (Millipore, Bedford, MA), blocked for 1 h with 4% BSA in PBS, and then incubated overnight at 4°C in PBS with a mouse monoclonal or rabbit polyclonal antibody that selectively recognizes phosphorylated ERK1/2 (1:2000; Santa Cruz Biotechnology) or CREB (1:1000; Upstate Biotechnology). After incubation with the primary antibody, the membrane was washed three times with PBS. The blots were subsequently exposed to a donkey anti-rabbit or sheep anti-mouse IgG peroxidase-linked antibody (1:2000; Amersham Biosciences, Piscataway, NJ) for 1 h at room temperature. The blots were visualized by enhanced chemiluminescence using Kodak X-OMAT LS film (Eastman Kodak, Rochester, NY). The density of the immunoblots was determined by ImageQuant software (Amersham Biosciences). To control for protein loading, the membranes then were stripped with stripping buffer (100 mM mercaptoethanol and 2% SDS in 62.5 mM Tris-HCl, pH 6.8) for 30 min at 60°C and reprobed with rabbit polyclonal antibody raised against ERK (1:2000; Santa Cruz Biotechnology) or CREB (1:1000; Cell Signaling Technology, Beverly, MA). The density of the phosphorylated proteins in the immunoblot was normalized to total kinase levels and then expressed as a percentage of those in controls. All protocols complied with institutional guidelines and were approved by Animal Care Committees of Medical College, National Taiwan University.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Mechanism of Action of YC-1. It is known that YC-1 binds to an
allosteric site on sGC and sensitizes the enzyme toward its gaseous activators
NO and carbon oxide (CO) by increasing the maximal catalytic rate
(Zabel et al., 1998;
Zhao et al., 1998). We thus
investigated the role of NO in the mechanism of action of YC-1 on the
enhancement of LTP at weak tetanus (50 Hz for 0.5 s) in hippocampal slices. As
shown in Fig. 3a, concomitant
administration of YC-1 and NOS inhibitor
NG-nitro-L-arginine-methylester
(L-NAME,; 300 µM) significantly attenuated the enhancement
effect of YC-1. On the other hand, zinc protoporphyrin (1 µM), a heme
oxygenase inhibitor, did not affect LTP induction by YC-1
(Fig. 3b). Thus, the LTP
enhancement of short-term treatment with YC-1 involves processes that are NO-
but not CO-dependent.
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The principal effector of NO in many tissues is sGC. Through binding to the
heme region of sGC, NO triggers the production of cGMP
(Wolin et al., 1982). In view
of the finding that NO enhances LTP in part by activating sGC
(Zhuo et al., 1994;
Arancio et al., 1995;
Son et al., 1998;
Lu et al., 1999), we examined
the possible involvement of cGMP in the enhancement effect of YC-1 on LTP.
Concomitant treatment of YC-1 with 1
H-[1,2,4]-oxadiazolo(4,3-a)-quinoxalin-1-one (ODQ; 5 µM), a
specific inhibitor of sGC (Garthwaite et
al., 1995), completely blocked LTP (107.8 ± 3.9%,
n = 5; Fig. 4a),
consistent with the idea that sGC is involved in both the induction of LTP and
the enhancement of LTP by YC-1. The downstream target of cGMP, PKG, is known
to contribute to LTP in the hippocampus
(Zhuo et al., 1994;
Arancio et al., 1995;
Son et al., 1998;
Lu et al., 1999;
Arancio et al., 2001). We
therefore examined the effects of a PKG inhibitor, KT5823, on enhancement of
LTP by YC-1. As shown in Fig.
4b, simultaneous perfusion of KT 5823 (2 µM) produced a
significant inhibition of LTP induced by YC-1 (112.5 ± 6.7%; n
= 5). One protein kinase family that has been implicated in the expression of
LTP is the ERKs. Concomitant application of ERK kinase inhibitor PD98059 (10
µM) with YC-1 also significantly antagonized LTP potentiating action of
YC-1 (Fig. 4c). Our results
suggest that the NO-cGMP-PKG-ERK signaling pathway is involved in the
enhancement of LTP by YC-1.
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The activation of NOS is Ca2+-dependent and the
influx of Ca2+ through NMDA receptor is essential for
induction of LTP in the hippocampal Schaffer collateral-CA1 pathway. As shown
in Fig. 5a, the presence of
2-amino-5-phosphonopentanoic acid (AP-5; 100 µM), an antagonist of NMDA
receptors, attenuated the amplitude of LTP by YC-1 at weak tetanus
stimulation, suggesting that certain consequences brought about by NMDA
receptor activation, presumably Ca2+ influx, play a role
in the LTP induced by YC-1. Consistent with the involvement of metabotropic
receptor in LTP, 
-methyl-4-carboxyphenylglycine (MCPG; 100 µM) also
significantly attenuated the amplitude of LTP by YC-1
(Fig. 5b). Simultaneous
application of AP-5 and MCPG markedly antagonized LTP induced by YC-1 at weak
tetanic stimulation (Fig. 5b;
112.4 ± 5.2%, n = 5).
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Effects of YC-1 on the Synaptic Plasticity in the Presence of NO Donor. NO is released by NOS, which is activated by Ca2+ influx upon high-frequency tetanic stimulation. We therefore investigated the downstream mechanism of YC-1 by the addition of NO donor to hippocampal slices to mimic high frequency stimulation. As shown in Fig. 6, we delivered a basal electrical stimulation at 0.02 Hz throughout the whole experimental period for the monitoring of the synaptic response in the presence of YC-1 (1.6 µM) and NO donor sodium nitroprusside (300 µM). It was found that concurrent perfusion of YC-1 with sodium nitroprusside for 6 min resulted in the induction of LTP at basal stimulation, indicating that NO donor is able to mimic the action of high frequency tetanic stimulation in the presence of YC-1. YC-1 or sodium nitroprusside alone had no effect on synaptic transmission at stimulating frequency of 0.02 Hz.
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It has been reported that the ERK cascade is essential for long-term
synaptic plasticity and for certain types of learning
(English and Sweatt, 1997;
Blum et al., 1999).
Furthermore, the transactivation of CREB by ERK plays an essential role in
synaptic plasticity and memory formation
(Impey et al., 1999). We thus
examined the effect of YC-1 on the phosphorylation of ERK and CREB in the
presence of NO donor in unstimulated hippocampal slices. As shown in
Fig. 7, little fluorescence was
detected in CA1 area of control hippocampal slices. However, incubation of
hippocampal slices with YC-1 (1.6 µM) and sodium nitroprusside (300 µM)
for 15 min markedly enhanced the fluorescence of pERK and pCREB. We then used
Western blotting analysis to examine the effect of YC-1 on the activation of
ERK and CREB. The floating hippocampal slices were treated with YC-1 (1.6
µM) and sodium nitroprusside (300 µM) for 15 min and then were used for
the detection of pERK and pCREB by Western blot. As shown in
Fig. 8a, pERK antibody yielded
two bands of 42 and 44 kDa corresponding to ERKs 2 and 1, respectively.
Immediately after the application of YC-1 plus nitroprusside for 15 min, we
observed a significant increase in pERK 1 and pERK 2 relative to control
slices. Densitometric analysis revealed an increase in pERK 1 and pERK 2 (238
± 30 and 177 ± 32% of control for pERK 1 and pERK 2,
respectively; n = 4) (Fig.
8a). The increase of pERK was inhibited by concomitant treatment
with PKG inhibitor 2 µM KT5823 (165 ± 33 and 134 ± 25% of
control for pERK 1 and pERK 2, respectively; n = 4). Furthermore,
CREB phosphorylation of un-stimulated hippocampal slices was also enhanced by
the treatment of YC-1 (1.6 µM) and sodium nitroprusside (300 µM), which
was also antagonized by PKG inhibitor KT5823 (2 µM)
(Fig. 8b). These results
indicate that ERK-CREB activation may be the downstream target of PKG in
response to the action of YC-1.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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;
Hawkins et al., 1996; Teledgy and
Kokavszky, 1997; Prast and
Philippu, 2001). In general, the relation between synaptic
plasticity and various forms of learning has been investigated by inhibiting
synaptic plasticity in a living animal and examine the consequences on later
retention behavior. In the present study, we have demonstrated that YC-1
enhances synaptic plasticity of hippocampus through a NO-dependent
pathway.
The novel compound YC-1 turns CO and NO into potent activators of sGC,
leading to an increase of 100- to 1000-fold in enzyme activity
(Friebe et al., 1996). Binding
of YC-1 to an allosteric site on sGC sensitizes the enzyme toward its gaseous
activators by reducing the ligand dissociation rate from the heme group
(Friebe et al., 1998). To
investigate a possible role for CO in the enhancement of LTP by YC-1, we have
blocked the production of CO in hippocampal slices. Heme oxygenase inhibitor
zinc protoporphyrin-IX did not affect LTP induced by weak tetanus paired with
YC-1 administration, suggesting that CO may not be involved in the LTP
potentiation of YC-1.
The involvement of NO in the action of YC-1 was indicated by the finding
that LTP induction by weak tetanus paired with the YC-1 treatment was markedly
inhibited by NOS inhibitor L-NAME. Moreover, LTP can be induced by
weak stimulation even at a frequency as low as 0.02 Hz when paired with the NO
donor sodium nitroprusside in the presence of YC-1. Both GC inhibitor ODQ and
PKG inhibitor KT5823 inhibited the enhancement of LTP by YC-1, suggesting that
the NO-cGMP-PKG pathway mediated the influence of YC-1 on synaptic plasticity.
It has been demonstrated that NO may be particularly important in regulating
the threshold of LTP induction, because NOS inhibitors blocked LTP induced by
weak, but not strong, afferent stimulation in CA1
(O'Dell et al., 1994;
Malen and Chapman, 1997;
Zhuo et al., 1998;
Lu et al., 1999). Here we
showed that YC-1 induced LTP at weak tetanus by amplifying the signal
transduction of NO, indicating that YC-1 also lowers the threshold for LTP
induction.
We found that weak tetanic stimulation at 50 Hz for 0.5 s did not induce
LTP unless YC-1 was present. The role of Ca2+ release
from intracellular stores has been implicated in hippocampal CA1 plasticity
(Wang et al., 1996). Treatment
of either AP5 or MCPG alone attenuated the enhancement of LTP by YC-1.
However, simultaneous treatment of both antagonists abolished the action of
YC-1 on LTP. These results suggest that Ca2+ influx from
NMDA receptor and inositol trisphosphate-induced Ca2+
release through metabotropic glutamate receptors all contribute to the
enhancement of LTP by YC-1. Increase of cytosolic Ca2+
is thus necessary for the activation of NOS to produce NO and for the full
expression of the action of YC-1. Our findings that YC-1 did not enhance LTP
when applied 10 min after weak tetanus (50 Hz for 0.5 s) is consistent with
the short-lifetime of NO released by weak tetanus, the NO-dependent action of
YC-1, and also the finding that PKG activator does not cause LTP when applied
5 min after weak tetanus (50 Hz for 0.5 s) in the CA1 region of guinea pig
hippocampal slices (Zhuo et al.,
1994). NO diffusion is spatially restricted and NO production
requires a minimum level of synaptic activity, which limits the synapses
modified by NO to the activated pathway only
(Hawkins et al., 1993). This
property of NO allows YC-1 to enhance LTP in an input-specific manner; hence,
its influence on behavior is experience-dependent. Nitric oxide induces
cytosolic production of cGMP, which modulates synaptic functions, leading to
the early phase of LTP (Hawkins et al.,
1998).
There is abundant cross-talk between kinase pathways, suggesting that ERK
may be a point of convergence integrating signals of protein kinase C, protein
kinase A, and Ca2+-calmodulin-dependent protein kinase
(Roberson et al., 1999;
Vanhoutte et al., 1999), in
addition to the activity of individual signaling systems. The NO-cGMP-PKG
pathway may also contribute to the late phase of LTP by causing induction of
immediate early genes through phosphorylation of CREB
(Gudi et al., 1996). CREB
phosphorylation and gene induction are thought to contribute to the late,
protein synthesis-dependent phase of hippocampal LTP
(Bourtchouladze et al., 1994;
Carew and Sutton, 2001), which
may involve presynaptic as well as postsynaptic changes
(Lu et al., 1999). Inhibition
of ERK phosphorylation and nuclear translocation prevents CREB phosphorylation
and results in rapidly decaying LTP (Davis
et al., 2000). Our study shows that ERK and its downstream
transcription factor CREB are rapidly phosphorylated after treatment of YC-1
in the presence of NO donor. The phosphorylation of both ERK and CREB by YC-1
plus NO donor was inhibited by PKG inhibitor KT5823, suggesting that
PKG-ERK-CREB pathways are involved in the LTP potentiating action of YC-1. The
relation between LTP and memory is a focus of intensive investigation
(Malenka and Nicoll, 1999).
Nitric-oxide synthase inhibitors reduce the capability of treated animals to
acquire or retain information in several learning tasks
(Prast and Philippu, 2001).
Our preliminary results show that administration of YC-1 greatly improved
learning and memory in several tasks involving different brain regions (data
not shown).
In conclusion, the results of the present study show that YC-1 enhances LTP in both hippocampal and amygdala slices. The remarkable characteristics of YC-1 in potentiating NO-stimulated GC activity during the induction of activity-dependent synaptic plasticity and the high spatial and temporal specificity of NO-induced cellular actions warrant that YC-1 will enhance acquisition of new information without affecting previously consolidated memory and suggest that NO-GC activators may be good candidates for new therapeutic drugs aiming at improving learning and memory in humans.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: LTP, long-term potentiation; NMDA,
N-methyl-D-aspartate; NO, nitric oxide; NOS, nitric-oxide
synthase; sGC, soluble guanylyl cyclase; PKG, cGMP-dependent protein kinase;
YC-1, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole; ACSF, artificial
cerebrospinal fluid; CREB, cyclic AMP response element-binding protein; fEPSP,
field excitatory postsynaptic potential; PBS, phosphate-buffered saline; ERK,
extracellular signal-regulated kinase; PMSF, phenylmethylsulfonyl fluoride;
L-NAME,
NG-nitro-L-arginine-methylester; ODQ, 1
H-[1,2,4]-oxadiazolo(4,3-a)-quinoxalin-1-one; KT5823,
(9S,10R,12R)-2,3,9,10,11,12,
hexahydro-10-methoxy-2,9-dimethyl-1-ox0–9.12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic
acid methyl ester; PD98059, 2'-amino-3'-methoxyflavone; AP-5,
2-amino-5-phosphonopentanoic acid; MCPG,
-methyl-4-carboxyphenylglycine.
Address correspondence to: Wen-Mei Fu, Pharmacological Institute, College of Medicine, National Taiwan University, 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan. E-mail: wenmei{at}ccms.ntu.edu.tw
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), YC-1 (1.6
µM; 
) enhanced LTP when perfused 3 min before and 3 min after tetanus
as shown by horizontal bar (a) but not when perfused 10 min after tetanus (b).
c, YC-1 (1.6 µM) given 3 min before and 3 min after weak tetanus (once at
50 Hz for 0.5 s) potentiated the induction of LTP. Inset, representative
fEPSPs before and 45 min after tetanus in YC-1-treated hippocampal slice are
shown. Scale bar: 4 ms, 2 mV. (n = 5
