 |
 Previous Article | Next Article 
The Journal of Neuroscience, November 15, 1999, 19(22):9788-9802
Dopamine Receptors and Groups I and II mGluRs Cooperate for
Long-Term Depression Induction in Rat Prefrontal Cortex through
Converging Postsynaptic Activation of MAP Kinases
Satoru
Otani1,
Nathalie
Auclair1,
Jean-Marie
Desce1,
Marie-Paule
Roisin2, and
Francis
Crépel1
1 Laboratoire de Neurobiologie et Neuropharmacologie du
Développement, Institut des Neurosciences, Université de
Paris VI, 75005 Paris, France, and 2 Laboratoire de
Signalization Cellulaire et Parasites, Hôpital Cochin, 75014 Paris, France
 |
ABSTRACT |
Tetanic stimuli to layer I-II afferents in rat
prefrontal cortex induced long-term depression (LTD) of layer I-II to
layer V pyramidal neuron glutamatergic synapses when tetani were
coupled to bath application of dopamine. This LTD was blocked by the
following metabotropic glutamate receptor (mGluR) antagonists coapplied with dopamine: (S)- -methyl-4-carboxyphenylglycine
(MCPG; group I and II antagonist),
(RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; group I
antagonist), or (RS)--methylserine-O-phosphate monophenyl ester (MSOPPE; group II antagonist). This suggests that the
dopamine-facilitated LTD requires synaptic activation of groups I and
II mGluRs during tetanus. LTD could also be induced by
coupling tetani to bath application of groups I and II mGluR agonist
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic
acid (1S,3R-ACPD). In the next series of
experiments, coapplication of dopamine and 1S,3R-ACPD, but not application of either
drug alone, consistently induced LTD without tetani or even single test
stimuli during drug application, suggesting that coactivation of
dopamine receptors and the mGluRs is sufficient for LTD induction.
Immunoblot analyses with anti-active mitogen-activated protein kinases
(MAP-Ks) revealed that D1 receptors, D2 receptors, group I mGluRs, and
group II mGluRs all contribute to MAP-K activation in prefrontal
cortex, and that combined activation of dopamine receptors and mGluRs synergistically or additively activate MAP-Ks. Consistently, LTD by
dopamine + 1S,3R-ACPD coapplication, as
well as the two other forms of LTD (LTD by dopamine + tetani and
LTD by 1S,3R-ACPD + tetani), was blocked by bath application of MAP-K
kinase inhibitor PD98059. LTD by dopamine + 1S,3R-ACPD coapplication was also blocked by postsynaptic injection of synthetic MAP-K substrate peptide. Our
results suggest that dopamine receptors and groups I and II mGluRs
cooperate to induce LTD through converging postsynaptic activation of
MAP-Ks.
Key words:
long-term depression; long-term potentiation; synaptic
plasticity; prefrontal cortex; dopamine; metabotropic glutamate
receptor; MAP kinase; learning and memory; schizophrenia
| |
INTRODUCTION |
Critical modulation of prefrontal
cognitive function by dopaminergic input arising from ventral tegmental
area (Glowinski et al., 1984 ; Kolb, 1984; Kuroda et al., 1996) is well
documented in rats (Simon et al., 1980; Zahrt et al., 1997),
primates (Sawaguchi and Goldman-Rakic, 1994; Goldman-Rakic, 1995), and
humans (Barchas et al., 1994; Iversen, 1995; Okubo et al., 1997).
Dopaminergic modulation on synaptic models of neuronal plasticity,
long-term potentiation (LTP), and long-term depression (LTD) (Hirsch
and Crepel, 1990) (for review, see Bliss and Collingridge, 1993; Otani and Ben-Ari, 1993; Bear and Abraham, 1996) have been also reported in
rat prefrontal cortex, where dopamine facilitates induction of LTD, but
not LTP, through D1 and D2 receptor activation (Law-Tho et al., 1995;
Otani et al., 1998b).
Many studies demonstrated roles of metabotropic glutamate receptors
(mGluRs) (Nicoletti et al., 1996; Conn and Pin, 1997) in LTP and LTD
(Aniksztejn et al., 1992; Bashir et al., 1993; Kato, 1993; Huang et
al., 1997; Oliet et al., 1997; Manahan-Vaughan et al., 1998; Otani and
Connor, 1998). In prefrontal cortex, LTP by theta burst stimulation is
blockable by group I and II mGluR antagonist
(S)--methyl-4-carboxyphenylglycine (MCPG) (Vickery et al., 1997). It is thought that MCPG blocks LTP through acting on
postsynaptic group I mGluRs (Vickery et al., 1997; Morris et al.,
1998). Indeed, group I mGluRs exist abundantly in postsynaptic elements
throughout cortex and other structures (Romano et al., 1995). More
specifically, the mGluR5 seems to exist on dendritic spines and shafts,
as well as on the membrane between spines, of cortical pyramidal
neurons (Romano et al., 1995), whereas the mGluR1 is present in
nonpyramidal neurons in cortex (Fotuhi et al., 1993). A recent
demonstration also suggests postsynaptic existence, as well as
presynaptic existence as classically viewed, of group II mGluRs in
cortex and other structures (Petralia et al., 1996). Localization of
group III mGluRs is still largely regarded as presynaptic [Gereau and
Conn (1995); Jin and Daw (1998); but see Bradley et al. (1996)].
Dopamine D1 receptors exist on dendritic spines and shafts of pyramidal
neurons in monkey frontal cortex layers II and V (Smiley et al., 1994;
Bergson et al., 1995). Importantly, these D1 receptors appear to be
colocalized with functioning glutamate receptors within the same
spines-shafts, although dopaminergic presynaptic terminals may not
have a direct contact with these postsynaptic elements, suggesting that
dopamine receptors extrasynaptically receive neurotransmitter dopamine
(Smiley et al., 1994). Colocalization of dopamine (at least D1) and
glutamate receptors in the same spines-shafts points to the
possibility that these two types of receptors interact with each other
postsynaptically. If it is the case, such an interaction may play a
role in prefrontal LTD induction. We have shown that prefrontal LTD,
whose induction is facilitated by dopamine, does not require activation
of NMDA receptors (Otani et al., 1998b) but still requires postsynaptic Ca2+-dependent processes (Otani et al.,
1998b). Therefore, in this paper, we investigated involvement of mGluRs
in prefrontal LTD induction.
Preliminary data have been published previously in abstract form (Otani
et al., 1998a,c).
| |
MATERIALS AND METHODS |
Slice preparation and electrophysiology. Male Sprague
Dawley rats (23-30 d old) were decapitated, and their brains were
removed. Coronal slices (300-400 µm; 2.2-3.7 mm from bregma) were
sectioned by the use of a Campden Vibratome in chilled (~0°C)
oxygenated (95% O2/5%
CO2) artificial CSF (ACSF) of the
following composition (in mM): NaCl 124, KCl 2, NaHCO3 26, KH2PO4 1.15, MgCl2 1, CaCl2 2, and
D-glucose 11. The slices were allowed to recover for at least 2 hr at room temperature (~20°C) in a chamber filled with continuously oxygenated ACSF. A slice was then transferred to a
submerged-type recording chamber where it was perfused with ACSF
(28°C) at the rate of 1 ml/min.
Stable intracellular recordings were made with sharp, glass
micropipettes filled with 3 M K-acetate (80-120 M tip
resistance) from the soma of >120 layer V pyramidal neurons in the
prelimbic area of prefrontal cortex. Negative currents were initially
injected by the use of an Axoclamp 2A amplifier, but after
stabilization of the cells, most or all currents were removed. The
cells had mean resting membrane potential of  71 ± 0.6 mV (SEM)
with input resistance 60 ± 2.5 M. Mean membrane potential held
during experiments was 74 ± 0.5 mV. A spike height of at least
70 mV was required to continue experiments. Only cells that remained
within 10% of changes from the initial values of membrane potential,
spike height, and input resistance were included for later analysis.
The mode of spike discharge was routinely examined before experiments
by the application of a depolarizing current step (500 msec) from resting membrane potential. Amplitude of the depolarizing step was set
so that a 30 msec application at that amplitude charges the cell to
fire one action potential. Of the neurons tested, 59% were classified
as regular spiking cells, and 18% were classified as bursting cells.
Five percent of the neurons showed a burst firing followed by regular
spiking with adaptation. The remaining 18% showed a few sporadic
spikes before a strong adaptation ceased spiking. As in the
study of Law-Tho (1995) and our previous study (Otani et al., 1998b),
there was no correlation between a discharge mode and the degree of
synaptic plasticity induction.
A bipolar, Teflon-coated tungsten stimulating electrode (external
diameter 125 µm) was placed on layer I-II (immediately interior to
pial surface) of the prelimbic area. The EPSP of 5-10 mV
amplitude was evoked at 0.033 Hz by the application of monophasic
square voltage pulses (100 µsec; Digitimer isolated stimulator). The responses were fed to an Axoclamp 2A amplifier at current-clamp mode,
digitized at 5-10 kHz with a Labmaster interface, and stored in an
on-line IBM computer for later analyses (ACQUIS1 program, developed by
G. Sadoc, Institut Alfred Fessard, CNRS, Gif sur Yvette, France).
Synaptic responses evoked by high-frequency stimulation were stored on
a magnetic tape by the use of a SONY PCM-701ES and a Betamax SL-HF100F.
LTD-inducing tetanic stimuli consisted of four trains of 50 Hz stimuli
(100 pulses), delivered at 0.1 Hz. The 0.033 Hz test stimuli were
resumed 30 sec after tetanic stimulation. All experiments were
performed in the presence of the GABA-A antagonist bicuculline
methiodide (1 µM) in bathing medium.
For the analysis of single EPSPs, we measured initial rising slope (the
 1 msec period from its onset; millivolts per milliseconds), which
contains only the monosynaptic component of the responses (Hirsch and
Crepel, 1990). To express changes of the EPSP slope, we averaged
responses from the 10 min period just before tetani-drug application (baseline) and also from the 35-40 min period after tetani-drug application. We calculated percentage decreases-increases of the initial slope from the baseline value. These percentage decreases-increases were compared among different groups. For the
analysis of synaptic responses evoked by high-frequency stimuli, we
measured the number of spikes, the number of the EPSPs whose amplitudes
were >50% of the first EPSP in the given episode of high-frequency
stimuli, and 90% decay time from peak membrane potential (Otani et
al., 1998b). Statistical analyses (two-tailed Student's t
test) were performed with p < 0.05 considered as
significant. All values were expressed as mean ± SEM.
In many experiments, biocytin (1.5%; Sigma, St. Louis, MO) was
included in recording electrodes and injected into cells by passing
positive current steps (~0.5 nA, 500 msec at 1 Hz for at least 10 min) at the end of experiments. The slices were fixed in 4%
paraformaldehyde dissolved in potassium PBS (0.01 M) for at
least overnight. They were then washed in the PBS solution three times
(10 min each) and placed in 1 ml of 0.1% PBS-Triton X-100 solution
containing 25 µl of solutions A and B (peroxidase standard PK-4000;
Vectastain ABC Kit, Vector Laboratories, Burlingame, CA) for up to 48 hr. The slices were washed again in PBS solution. They were then placed
in diaminobenzidine tetrahydrochloride (DAB) solution (Peroxidase
Substrate Kit, SK-4100, Vector) for 10 min. The slices were washed
three times in PBS solution before being mounted on microscope slides.
Drugs used in the electrophysiological studies were
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid
(1S,3R-ACPD; Tocris Cookson, Bristol, UK),
(RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; Tocris
Cookson), ascorbic acid (Sigma), bicuculline methiodide (Tocris
Cookson), BAPTA (Research Biochemicals International, Natick, MA),
2S,2'R,3'R-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV; Tocris Cookson), S-3,5-dihydroxyphenylglycine
(DHPG; Tocris Cookson), dopamine (Sigma),
(S)--methyl-4-carboxyphenylglycine (MCPG; Tocris Cookson),
(RS)--methylserine-O-phosphate monophenyl ester (MSOPPE;
Tocris Cookson), mitogen-activated protein kinase substrate peptide
Ala-Pro-Arg-Thr-Pro-Gly-Gly-Arg-Arg (Alexis Biochemicals), PD98059
(2'-amino-3'-methoxyflavone; Alexis Biochemicals). All drugs were
applied in perfusing medium, except for BAPTA and MAP-K peptide, which
were included in recording electrodes and injected to postsynaptic
cells. Dopamine was dissolved in ascorbic acid solution (20 µM; Sigma) to reduce oxidization of the compound.
Biochemical analyses. For a separate series of experiments
to bioassay MAP-Ks, coronal brain slices were prepared identically as
described above. After a recovery period (>2 hr), a slice was transferred to a well (~10 ml volume) filled with oxygenated ACSF (28°C) containing 1 µM bicuculline methiodide. After a
10 min incubation with bicuculline, the slice was transferred to a
separate well that additionally contains dopamine alone, dopamine with SCH23390 (D1 antagonist; Research Biochemicals International) and/or
()-sulpiride (D2 antagonist; Sigma), dopamine with one of the
following mGluR agonists, 1S,3R-ACPD, DHPG, and
DCG IV, or one of the mGluR agonists alone. There, the slice was
incubated for either 2 or 5 min in the drug-containing experimental
solution. Separate slices that were only incubated in
bicuculline-containing ACSF (10 min) served as control. Bicuculline
itself did not modify activity of MAP-Ks. Some other slices were
incubated in the bicuculline-ACSF for 10 min and then in the
experimental ACSF for 10 min, before they were retransferred to the
bicuculline-ACSF for either 2, 15, or 60 min. At the end of a given
incubation period, the prelimbic area of both hemispheres was removed
and stored at 20°C for later analyses.
Immunoblot analysis of MAP-Ks was performed as described by Towbin et
al. (1979). Frozen slices were rapidly thawed and homogenized at 4°C
in 20 µl of lysis buffer containing 1% nonidet P-40, 1% deoxycholic
acid, 0.1% SDS, 158 mM NaCl, 10 mM Tris, pH
7.8, 1 mM phenylmethylsulfonyl fluoride, and 1 mM Na3VO4 (RIPA
buffer), stirred for 20 min at 4°C, and centrifuged for 15 min at
12,000 × g. The protein concentration was determined
by the Bradford microassay method (Bradford, 1976) using  -globulin
as standard. Equal amounts of protein from lysates (50 µg) were
separated by electrophoresis on SDS-10% polyacrylamide gel and
transferred onto a nitrocellulose membrane. Membranes were incubated
for 2 hr at room temperature with 0.25% gelatin in Tris-buffered
saline (10 mM Tris-HCl, pH 7.5, 150 mM NaCl) containing 0.05% Tween 20 (TBST) to
block non-specific binding sites, and then for 2 hr with the polyclonal
anti-active MAP kinase antibody (anti-ERKs) at 1:20,000 (Promega,
Madison, WI), which recognizes dually phosphorylated MAP-Ks p44 and
p42. After extensive washing steps with TBST, the membranes were
incubated for 2 hr with horseradish peroxidase-conjugated goat
anti-rabbit IgG (Dako, Glostrup, Denmark) at a dilution of 1:5000, then
washed with blocking buffer. Proteins were visualized after a
chemiluminescence staining following the manufacturer's protocol (ECL,
Amersham, Arlington Heights, IL). Immunoreactive bands were analyzed by
means of densitometry with a scanner, and their intensity was
quantified using NIH image 1.61 software.
Reprobing with specific antibodies was performed after incubation for 2 hr at 65°C in 200 mM glycine, pH 2.5, containing 1% SDS,
followed by two washes with 1 M Tris-HCl, pH 8, and one
wash with TBST. The membrane was then incubated with the polyclonal anti-ERK2 C-14 antibody (at 1:1000; Santa Cruz Biotechnology, Santa
Cruz, CA), which recognizes ERK2/p42 and weakly ERK1/p44.
| |
RESULTS |
LTD induction in the presence of dopamine requires synaptic
activation of mGluRs
Figure 1A shows a
representative layer V pyramidal neuron stained with biocytin, and
Figure 1B shows our experimental configuration. As we
have shown previously (Otani et al., 1998b), tetanic stimuli (50 Hz,
100 pulses × 4 in 10 sec intervals) delivered to layer I-II
fibers at the end of 10-15 min bath application of dopamine (100 µM in 20 µM ascorbic
acid) induced LTD of the monosynaptic component of the EPSP recorded
from the soma of layer V pyramidal neurons (Fig. 1E)
(22 ± 7.6% decrease over baseline, measured during
the 35-40 min period after tetani; n = 14, p < 0.002 vs control group shown in Fig.
1C). The tetani alone did not induce any lasting synaptic
changes (0.7 ± 1.1%, n = 11) (Fig.
1C), whereas dopamine application alone only transiently
depressed synaptic transmission, which recovered fully within 30 min
(4.7 ± 7.0% measured 35-40 min after the beginning of washout,
n = 5) (Fig. 1D).
View larger version (78K):
[in this window]
[in a new window]
|
Figure 1.
Dopaminergic facilitation of LTD induction in
layer I-II to layer V pyramidal neuron glutamatergic synapses in rat
prefrontal cortex. A, Photo image of a representative
neuron stained with biocytin. B, Schematic
representation of experimental protocol used for electrical
measurement. C, Application of 50 Hz tetanic stimuli to
layer I-II fibers did not induce lasting synaptic changes (0.7 ± 1.0% over baseline measured at 35-40 min after tetani,
n = 11). D, Bath application of
dopamine (100 µM in 20 µM ascorbic acid,
10-15 min) acutely depressed the synaptic responses, but the
depression fully recovered within 30 min after dopamine washout
(4.7 ± 7.0% over baseline measured at 35-40 min after washout,
n = 5). E, Application of tetanic
stimuli in the presence of dopamine induced LTD [22 ± 7.6%
over baseline measured at 35-40 min after tetani-washout,
n = 14, p < 0.002 vs control
(C)]. Averaged synaptic responses taken from the
indicated time points in this condition are superimposed and shown in
the inset in E.
|
|
To test whether this LTD induction facilitated by dopamine requires
synaptic activation of mGluRs, we first used the broad spectrum mGluR
antagonist MCPG (300-500 µM), which acts on both group I
and group II mGluRs. MCPG was coapplied to the bath with dopamine. At
the end of the 10-15 min application period, during which dopamine
exerted its acute depressant effect on the synaptic responses (Fig.
2A), tetanic stimuli at
50 Hz were delivered (n = 5) (Fig.
2A). Test stimulation was resumed 30 sec after the last train of tetanus. Synaptic responses were followed for at least 40 min. Tetani in the presence of dopamine + MCPG failed to induce LTD
(Fig. 2A) [5.2 ± 6.5% change
over baseline, measured during the 35-40 min period after tetani-drug
washout; n = 5, p > 0.3 vs control
group in which tetani were delivered alone (0.7 ± 1.1%)]
(Fig. 1C). To test whether MCPG itself facilitates induction
of LTP to mask LTD, in another group of neurons (n = 5)
we applied MCPG alone for 10-15 min and delivered tetanic stimuli. In
three of five neurons, MCPG facilitated short-term plasticity induction
(potentiation in one case and depression in two cases), but never
facilitated long-term plasticity induction. Mean percentage changes of
the EPSP slope calculated from these five neurons are depicted in
Figure 2B (0.3 ± 3.8% over baseline at
35-40 min; n = 5, p > 0.9 vs
control). Thus, MCPG genuinely blocked LTD induction in the presence of
dopamine.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 2.
Dopaminergic facilitation of LTD is inhibited by
the presence of MCPG, the antagonist of group I and group II mGluRs.
A, MCPG (300-500 µM) was coapplied in the
bath with dopamine. The rest of the protocols are identical to those in
Figure 1E. MCPG blocked induction of LTD
[5.2 ± 6.5% 35-40 min after tetani-drug washout,
n = 5, p > 0.3 vs control
(Fig. 1C)]. Top traces are averaged
responses taken from the indicated time points. B, The
same tetanic stimuli in the presence of MCPG alone did not induce
lasting synaptic changes (0.3 ± 3.8% 35-40 min after
tetani-MCPG, n = 5, p > 0.9 vs control), suggesting that the block of dopamine-facilitated LTD by
MCPG (A) was not a masking of LTD. Top
traces are averaged synaptic responses taken from the indicated
time points.
|
|
Group I mGluRs are involved in LTD induction in the presence
of dopamine
We next used the specific antagonist of group I mGluRs AIDA (200 µM) (Moroni et al., 1997). AIDA was bath-applied with
dopamine for 10-15 min, and 50 Hz tetani were delivered at the end of
the coapplication (n = 5). AIDA also blocked LTD
induction in the presence of dopamine. We plotted average changes of
the EPSP slope calculated from the five cells in Figure
3A. Mean EPSP change occurring
during the 35-40 min period after tetani-drug washout (1.8 ± 6.0%, n = 5) shows no significant difference from mean value calculated from the same period in the control group (0.7 ± 1.1%; p > 0.1) (Fig. 1C), but it shows
a significant difference from that of the group in which dopamine
application alone was combined with tetani (22 ± 7.6%;
p < 0.025) (Fig. 1E). In another group of cells (n = 6), AIDA was applied alone to test
whether AIDA itself facilitates LTP to mask LTD. We plotted mean
percentage changes of the EPSP slope from six experiments under this
condition in Figure 3B. Mean change at the 35-40 min period
after tetani-drug washout is 1.3 ± 7.0%
(p > 0.9 vs control). Thus, the failure of AIDA
to induce lasting synaptic plasticity suggests that the block of LTD
with AIDA (Fig. 3A) cannot be attributed to a masking of
LTD.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 3.
Group I mGluR antagonist AIDA inhibits
dopaminergic facilitation of LTD. A, AIDA (200 µM) was bath-applied with dopamine for 10-15 min, and
tetanic stimuli were delivered (identical to Fig.
1E except the presence of AIDA). No LTD was
induced [1.8 ± 6.0% 35-40 min after tetani-drug washout,
n = 5, p > 0.1 vs control
(Fig. 1C), but p < 0.025 versus
dopamine + 50 Hz group (Fig. 1E)].
B, In a separate group of neurons, AIDA alone was
bath-applied, and tetani were delivered. Short-term changes occurred,
but no lasting synaptic changes were induced (1.3 ± 7.0%
35-40 min after tetani-AIDA, n = 6, p > 0.9 vs control), suggesting that the block of
LTD by AIDA (A) was not a masking of LTD.
Top traces are averaged synaptic responses taken from
the indicated time points.
|
|
Group II mGluRs are also involved in LTD induction in the presence
of dopamine
Next, we coapplied the selective group II mGluR antagonist MSOPPE
(200 µM) (Thomas et al., 1996) in the bath
with dopamine for 10-15 min before tetanic stimuli were delivered
(n = 7). In Figure
4A, we plotted mean
EPSP changes from these experiments. The EPSP slope change occurring
during the 35-40 min period after tetani-drug washout is 5.3 ± 3.1%, still showing no significant difference compared with the
control group (p > 0.1), but showing a
significant difference from the group in which dopamine application alone was combined with tetani (p < 0.04).
View larger version (29K):
[in this window]
[in a new window]
|
Figure 4.
Group II mGluR antagonist MSOPPE inhibits
dopaminergic facilitation of LTD. A, MSOPPE (200 µM) was bath-applied with dopamine for 10-15 min, and
tetanic stimuli were delivered (identical to Fig.
1E except the presence of MSOPPE). Tetani failed
to induce LTD [5.3 ± 3.1% 35-40 min after tetani-drug
washout, n = 7, p > 0.1 vs
control (Fig. 1C), but p < 0.04 versus dopamine + 50 Hz group (Fig. 1E)].
B, Tetanic stimuli in the presence of MSOPPE alone
induced some degree of post-tetanic changes in five of nine cases but
did not induce LTP on average. Mean percentage increase 35-40 min
after tetani-drug washout calculated from eight experiments was
0.6 ± 3.4% over baseline (recording of one cell that showed STP
discontinued 25 min after tetani; p > 0.7 vs
control depicted in Fig. 1C). Top traces
are averaged synaptic responses taken from the indicated time
points.
|
|
In a separate group of cells (n = 9) (Fig.
4B), the effect of MSOPPE alone on synaptic
plasticity was tested. Tetani delivered at the end of 10-15 min
application of MSOPPE were sometimes followed by potentiation (four of
nine cells) or depression (one of nine cells). In both cases, the EPSP
slope returned to control level within 30 min, except one case in which
some degree of lasting changes was still observed at 35-40 min after
tetani (16% increase). In Figure 4B, we plotted mean
changes of the EPSP slope calculated from eight experiments in which
intracellular recordings continued for 40 min after tetanic stimuli
[the recording of one cell that showed short-term potentiation (STP)
discontinued 25 min after tetani]. Because of the variability of the
changes in the responses after tetani, the graph shows large SEMs after
delivery of tetani. The variation and the post-tetanic effects,
however, decreased toward the end of recording, generating a mean EPSP
slope change of only 0.6 ± 3.4% during the 35-40 min period
after tetani-drug washout (p > 0.7 compared
with control, n = 8). These results suggest that the
blockade of LTD with MSOPPE (Fig. 4A) cannot be
explained by a masking of LTD.
Synaptic responses during 50 Hz stimuli in the presence of group II
mGluR antagonist
Presynaptic group II mGluRs use-dependently inhibit glutamate
release at least in certain synapses (Conn and Pin, 1997). Thus, the
group II antagonist MSOPPE may facilitate synaptic transmission during
tetanus. Postsynaptic depolarization then may exceed a degree optimal
for LTD induction, leading to a blockade of LTD. To test this
possibility, we analyzed synaptic responses during tetanus in the
presence of MSOPPE (n = 8) (see Fig.
4B for EPSP plots before and after tetani in this
group. Responses during tetanus in one cell could not be recorded
because of a technical failure). We measured the following three
parameters in high-frequency synaptic responses: (1) the number of
spikes per tetanus episode, (2) the number of the EPSPs per tetanus
episode whose amplitudes remained larger than 50% of the initial EPSP
evoked in that episode, and (3) 90% decay time from peak membrane
potential (spike threshold was taken when a spike(s) was present). On
average, MSOPPE increased the number of spikes
(p < 0.05 in all four train episodes) and the
number of EPSPs (p < 0.05 in the first train
episode; p < 0.1 in the second and fourth episodes)
evoked to a train of tetanus over control group (n = 12) (Fig. 5, insets). Ninety
percent decay time value did not show a significant difference on
average over control, but when the five cells in which a clear STP or
short-term depression was induced are taken into account, MSOPPE
increased 90% decay over control at least in the first tetanus episode
(2217 ± 606 vs 726 ± 228 msec, p < 0.02).
One typical example that shows increases in these three parameters is
shown and compared with a control cell in Figure 5. MSOPPE, in
contrast, did not change at least two postsynaptic parameters tested by
direct somatic current injections (0.5-0.6 nA for 500 msec), i.e.,
spike-train adaptation and afterhyperpolarization (n = 3; data not shown).
View larger version (22K):
[in this window]
[in a new window]
|
Figure 5.
MSOPPE, the group II mGluR antagonist, augments
synaptic responses during 50 Hz tetanic stimuli, compared with control
condition (see Fig. 4B for plots of EPSP slope
before and after tetani in this MSOPPE condition). Traces shown in this
figure are the synaptic responses evoked by the first of four episodes
of tetanic stimuli in two different cells. On average, MSOPPE (200 µM, n = 8) increased the number of
spikes (p < 0.05 in all four train
episodes) and the number of the EPSPs whose amplitudes were larger than
50% of the first EPSP evoked in the given train episode
(p < 0.05 in the first train episode,
p < 0.1 in the second and fourth episodes). Ninety
percent decay time from peak membrane depolarization was, on average,
not different from control, but if five cells that showed clear
post-tetanic changes (see Results) are taken into account,
MSOPPE increased 90% decay over control in the first tetanus episode
(2217 ± 606 msec vs 726 ± 228 msec, p < 0.02). The MSOPPE-treated cell shown in this figure is a cell that
showed clear increases in all three of these parameters. MSOPPE did not
reduce spike-train adaptation and afterhyperpolarization tested with
postsynaptic current injection (data not shown). It is unlikely,
however, that this augmentation of synaptic responses during tetanus by
MSOPPE per se is the mechanism by which MSOPPE blocked LTD in the
presence of dopamine (Fig. 4A), because dopamine
itself augmented synaptic responses during tetanus (Otani et al.,
1998b) and occluded the effect of MSOPPE. Insets show
the same responses by different scales of amplitude and time.
|
|
We next compared synaptic responses during tetanus in the presence of
MSOPPE + dopamine (no LTD condition) with those in the presence of
dopamine alone (LTD condition). Under this comparison, MSOPPE no longer
exerted significant changes in the high-frequency synaptic responses in
the above three parameters. In other words, the enhancing effects of
dopamine on these parameters (Otani et al., 1998b) are sufficient to
occlude the effects of MSOPPE.
In contrast to MSOPPE, the group I antagonist AIDA did not
significantly increase postsynaptic responses during tetanus.
Postsynaptic responses in the presence of AIDA + dopamine also did not
differ from those in the presence of dopamine alone.
Effects of mGluR agonists on synaptic responses and LTD
Results so far indicate that synaptic activation of groups I
and II mGluRs must occur for dopamine to facilitate LTD induction. In
separate groups of cells, we tested whether pharmacological activation
of mGluRs can also facilitate LTD by 50 Hz tetani, where 50 Hz tetani
alone do not induce lasting synaptic changes (Fig. 1C).
First, 1S,3R-ACPD (100 µM), the groups I and II mGluR agonist, was
applied for 10-15 min before delivery of tetani (n = 4). All four cells expressed LTD (Fig.
6A). Mean change of the
EPSP slope occurring during the 35-40 min period after tetani-drug washout was 37 ± 5.7% (n = 4, p < 0.001 vs control depicted in Fig. 1C).
As shown in Figure 6B, and as is the case in
hippocampus (Aniksztejn et al., 1992), sole application of
1S,3R-ACPD induced only a transient depression
that fully recovers within 30 min (3.4 ± 4.2% mean change at
35-40 min after washout; n = 4). Thus, pharmacological
stimulation of groups I and II mGluRs facilitates LTD induction.
View larger version (23K):
[in this window]
[in a new window]
|
Figure 6.
Simultaneous activation of group I and group II
mGluRs by 1S,3R-ACPD facilitates LTD
induction. A, Tetanic stimuli in the presence of
1S,3R-ACPD (100 µM, 10-15
min) induced LTD (n = 4). Mean LTD occurring 35-40
min after tetani-drug washout was 37 ± 5.7%
[(n = 4, p < 0.001 vs control
(Fig. 1, top right inset)]. Top traces
are averaged responses taken from time points 1 and
2. A superimposed representation of the responses
(1+2) is also shown. B, Bath application
of 1S,3R-ACPD (100 µM)
alone only transiently depressed synaptic responses, which fully
recovered within 30 min (n = 4; mean percentage
change of the EPSP slope 35-40 min after drug washout, 3.4 ± 4.2%).
|
|
Second, involvement of group I mGluRs in LTD induction was tested by
the use of specific group I mGluR agonist DHPG (100 µM) (Brabet et al., 1995; Sekiyama et al., 1996). First, as shown in Figure
7A (n = 4),
when applied alone (10-15 min), DHPG caused a transient depression of
the EPSP (Gereau and Conn, 1995), which is accompanied by several
postsynaptic parameter changes, including weak membrane depolarization
and a reduction in spike-train adaptation and afterhyperpolarization
(tested at membrane potential restored to resting level) (Fig.
7A, top traces) (cf. Vickery et al.,
1997). The depression of the EPSP fully recovered within 30 min (mean change at 35-40 min, 2.0 ± 4.5%, n = 4). In
another group of cells (n = 5) (Fig. 7B), 50 Hz tetani were applied at the end of DHPG application. DHPG did not
facilitate LTD induction (4.8 ± 7.1% at 35-40 min,
n = 5, p > 0.1 vs control). Thus, sole
activation of group I mGluRs is not sufficient to facilitate LTD.
View larger version (24K):
[in this window]
[in a new window]
|
Figure 7.
Sole activation of group I mGluRs with the agonist
DHPG is insufficient to facilitate LTD. A, In the first
group (n = 4), DHPG (100 µM, 10-15
min) was applied alone in the bath without tetani. DHPG induced a
transient synaptic depression that was accompanied by a mild (a few
millivolts) postsynaptic membrane depolarization and a reduction in
spike-train adaptation and afterhyperpolarization (shown in top
traces; membrane potential set at resting level). Mean change
of the EPSP slope 35-40 min after drug washout was 2.0 ± 4.5%
(n = 4). B, Tetanic stimuli in the
presence of DHPG failed to facilitate LTD induction. Mean change of the
EPSP slope 35-40 min after tetani-DHPG was 4.8 ± 7.1%
[n = 5, p > 0.1 vs control
(Fig. 1C)].
|
|
Third, effects of the potent group II mGluR agonist DCG IV (Ishida et
al., 1993) on the synaptic responses and LTD were tested. Application
of DCG IV [50-100 nM, concentrations two orders below that to activate NMDA receptors (>10 µM) (Ishida et al.,
1993; Wilsch et al., 1994)] acutely depressed the synaptic responses (25 ± 4.4% at the end of 10-15 min application,
n = 6) (Fig. 8A). The acute
depression was not accompanied by postsynaptic membrane depolarization
or changes in spike-train adaptation or afterhyperpolarization (Fig.
8A, top traces). Interestingly, the synaptic depression remained after washout of DCG IV, showing a
21 ± 3.8% mean LTD during the 35-40 min period after washout (n = 6) (Fig. 8A). In another group
of cells (n = 4), tetanic stimuli were applied at the
end of 10-15 min DCG IV application. Tetani did not augment LTD
expressed at 35-40 min after tetani-DCG IV washout (19 ± 7.1%, p > 0.8 compared with DCG IV group; data not
shown).
View larger version (29K):
[in this window]
[in a new window]
|
Figure 8.
Sole activation of group II mGluRs with potent
agonist DCG IV induces postsynaptic Ca2+-dependent
LTD without tetanic stimuli. A, Bath application of DCG
IV (50-100 nM) acutely depressed synaptic response that is
followed by a lasting depression. Mean change of the EPSP slope 35-40
min after drug washout was 21 ± 3.8% (n = 6). Top traces show that DCG IV did not change
spike-train adaptation and afterhyperpolarization. Superimposed
averaged synaptic responses taken from time points 1 and
2 are also shown. B, DCG IV-induced LTD
was absent in cells injected with BAPTA. BAPTA did not block acute
depressant action of DCG IV on the synaptic responses. Mean change of
the EPSP slope 35-40 min after DCG IV washout was 0.1 ± 2.2%
(n = 4, p < 0.005 vs above DCG
IV group). In a separate group of neurons (n = 4),
a late application of MSOPPE did not reverse the expression of DCG
IV-induced LTD (see Results for details), further suggesting that DCG
IV-induced LTD is not a result of insufficient washout of the
drug.
|
|
Two lines of evidence suggest that LTD induced by DCG IV is not
a result of insufficient washout from the acute depressant action of
the drug. First, as shown in Figure 8B, a previous
postsynaptic injection of Ca2+ chelator
BAPTA (100 mM in recording electrodes) completely
blocked LTD by DCG IV application (0.1 ± 2.2% mean EPSP change
at 35-40 min after drug washout, n = 4, p < 0.005 vs DCG IV group), but not the acute
depression by DCG IV (22 ± 2.1% at the end of 10-15 min
application). Diffusion of BAPTA was facilitated by steady negative
current injections through the recording electrodes (0.2-0.4 nA for at
least 30 min before drug application). Second, application of MSOPPE
(200 µM) did not reverse the expression of DCG
IV-induced LTD. MSOPPE (200 µM) was applied at
25 min after the beginning of DCG IV washout until the end of
recording. Depression expressed at 35-40 min after DCG IV washout in
the presence of MSOPPE was 17 ± 5.4% (n = 5, p > 0.5 vs DCG IV group; data not shown). These data
suggest that strong pharmacological stimulation of group II mGluRs can
by itself induce LTD. The BAPTA experiments further show that LTD
induced by DCG IV involves postsynaptic
Ca2+-dependent processes.
Coactivation of dopamine receptors and mGluRs is sufficient for
LTD induction
Dopamine sole application or 1S,3R-ACPD sole
application does not induce LTD (Figs. 1D,
6B), whereas 50 Hz stimuli combined with either drug
induce LTD (Figs. 1E, 6A). Does
then coapplication of these two agonists activate biochemical cascades
sufficient to induce LTD? To answer this question, dopamine (100 µM) and 1S,3R-ACPD (100 µM) were coapplied in the bath for 10-15 min
without delivery of tetanic stimuli (n = 5). In five of
five cases, clear LTD was induced. LTD occurring during the 35-40 min
period after the end of coapplication was 27 ± 2.6% (Fig.
9A)
(n = 5, p < 0.005 vs the
group in which dopamine was applied alone, and p < 0.001 vs the group in which ACPD was applied alone). In four other
cells, we tested whether 0.033 Hz single test stimuli during the drug
coapplication are necessary for this LTD. Thus, test synaptic
stimulation was halted just before coapplication of dopamine + 1S,3R-ACPD until 30 min after the beginning of
washout of the drugs. Under this condition, as shown in Figure
9B, coapplication of dopamine + 1S,3R-ACPD still induced LTD (29 ± 5.1%
35-40 min after washout, n = 4, p < 0.01 vs dopamine alone group, and p < 0.005 vs
1S,3R-ACPD alone group). In four other cells, we
halted test synaptic stimuli for 45 min (equivalent to the 15 min drug application-stimulus omission period plus the 30 min post-drug stimulus omission period in the above condition) to test whether omission of test stimuli itself causes decreases of synaptic responses. This was not the case (data not shown; 0.3 ± 5.2% during the period equivalent to 35-40 min after washout, p < 0.01 vs the group depicted in Fig. 9B). These results
suggest that LTD induced by coactivation of dopamine receptors and
groups I and II mGluRs requires neither stimulation of presynaptic
fibers nor the activation of other classes of postsynaptic receptors by
evoked transmitter release.
View larger version (21K):
[in this window]
[in a new window]
|
Figure 9.
Simultaneous activation of dopamine receptors and
mGluRs is sufficient for LTD induction. A, Bath
application (10-15 min) of dopamine (100 µM in 20 µM ascorbic acid) and
1S,3R-ACPD (100 µM) induced
synaptic depression that remained after washout of the drugs
[27 ± 2.6% 35-40 min after drug washout,
n = 5, p < 0.005 vs
dopamine-alone group (Fig. 1D) and
p < 0.001 vs
1S,3R-ACPD-alone group (Fig.
6B)]. B, Induction of LTD by
dopamine + ACPD coapplication did not require 0.033 Hz single test
synaptic stimuli (29 ± 4.2% 35-40 min after drug washout,
n = 4, p < 0.01 vs
dopamine-alone group and p < 0.005 vs
1S,3R-ACPD-alone group). Test stimuli
were halted just before application of the drugs until 30 min after the
beginning of drug washout. Halting of test stimuli itself did not
change synaptic responses (see Results). C, LTD was also
induced by coapplication of dopamine and group I agonist DHPG (100 µM) in four of five cells. The plots were made from all
five experiments (29 ± 8.9% 35-40 min after drug washout,
n = 5, p < 0.025 vs both DHPG
and dopamine groups). Thus, although LTD induced by 50 Hz tetani in the
presence of dopamine requires synaptic activation of group I
and group II mGluRs (Figs. 2A,
3A, 4A), and although 50 Hz tetani
in the presence of groups I and II agonist
1S,3R-ACPD, but not DHPG,
induce LTD (Figs. 6A, 7B),
pharmacological activation of group I mGluRs alone with DHPG, if
combined with dopamine application, can induce LTD. However, this LTD
induction is somewhat less consistent than that after groups I
and II mGluRs are coactivated with
1S,3R-ACPD (nine LTD of nine cases) (Fig.
9A,B).
|
|
In an additional group (n = 5) (Fig. 9C), we
tested whether sole stimulation of group I mGluRs with DHPG (100 µM) combined with dopamine application induces
LTD. In four of five cases, dopamine + DHPG coapplication resulted in
LTD (mean EPSP change 29 ± 8.9%, n = 5, p < 0.025 vs both DHPG and dopamine groups). Thus,
although LTD induced by 50 Hz in the presence of dopamine (Fig.
1E) requires synaptic activation of group I
and group II mGluRs (Figs. 2A,
3A, and 4A), and although 50 Hz tetani in
the presence of groups I and II agonist
1S,3R-ACPD, but not group I agonist
DHPG, induce LTD (Figs. 6A, 7B),
pharmacological activation of group I mGluRs alone with DHPG, if
combined with dopamine bath application, can preclude the requirement
for group II mGluR activation in LTD. However, it is important to note
that one of the five cells in the dopamine + DHPG group showed a
complete return to baseline level after drug washout (0.4% at 35-40
min), suggesting that concurrent activation of group I and
group II mGluRs with 1S,3R-ACPD facilitated LTD
more consistently (clear LTD in nine of nine cases; groups depicted in
Fig. 9A,B combined).
LTD in prefrontal cortex requires activation of MAP kinases
In the next series of experiments, we searched for a biochemical
manner where dopamine receptors and mGluRs cooperate to induce LTD. We chose to examine the participation of mitogen-activated protein
kinases MAP-Ks (also known as ERKs), because MAP-Ks occupy a position
where activation of many other second messengers, including protein
kinase C (PKC) and cAMP-dependent protein kinase A (PKA), converge to
exert their effects (Nestler and Greengard, 1994; Cobb and Goldsmith,
1995; Robinson and Cobb, 1997; Roberson et al., 1999). We used PD98059,
a cell-permeable specific inhibitor of MAP-K kinases 1 and 2 (MEK1 and
MEK2) (Alessi et al., 1995; Dudley et al., 1995). The MEKs specifically
activate ERK1 and ERK2, respectively (Cohen, 1997). The effect of
PD98059 was tested on three forms of LTD reported in this paper:
(1) LTD induced by 50 Hz stimuli in the presence of dopamine (Fig.
1E), (2) LTD induced by 50 Hz stimuli in the presence
of 1S,3R-ACPD (Fig. 6A), and
(3) LTD induced by coapplication of dopamine and
1S,3R-ACPD (Fig. 9A). PD98059 (20 µM) was bath-applied 15 min before application of dopamine (100 µM) or
1S,3R-ACPD (100 µM), or
both, until the end of the application-tetani. PD98059 neither
changed baseline synaptic responses during the preincubation period nor
affected the acute depression of synaptic responses by dopamine or
1S,3R-ACPD (Fig.
10). PD98059, however, completely
blocked induction of LTD by 50 Hz tetani in the presence of dopamine
(Fig. 10A) (0.3 ± 4.1% EPSP change
35-40 min after drugs-tetani, n = 6, p < 0.02 vs dopamine + tetani group depicted in Fig.
1E). Large post-tetanic potentiation was noted in
some cells of this group. Second, PD98059 completely blocked LTD by 50 Hz tetani in the presence of 1S,3R-ACPD (Fig. 10B) (0.6 ± 3.9% 35-40 min after
drugs-tetani, n = 4, p < 0.002 vs
1S,3R-ACPD + tetani group). Third, PD98059
completely blocked LTD by dopamine + 1S,3R-ACPD
(Fig. 10C) (4.9 ± 5.8% 35-40 min after drug
washout, n = 6, p < 0.02 vs dopamine + 1S,3R-ACPD group shown in Fig. 9A). In
addition, 50 Hz tetani in the presence of PD98059 alone did not induce
lasting synaptic changes (data not shown; 2.6 ± 3.9%,
n = 4).
View larger version (22K):
[in this window]
[in a new window]
|
Figure 10.
LTD induction in prefrontal cortex requires
activation of MAP-Ks. A, LTD by 50 Hz tetani in the
presence of dopamine (Fig. 1E) was blocked by
bath application of PD98059 (20 µM), the specific
inhibitor of MAP-K kinases (MEK1 and MEK2, which phosphorylate ERK1 and
ERK2). Mean change of the EPSP slope measured 35-40 min after drug
washout-tetani was 0.3 ± 4.1% (n = 6, p < 0.02 vs dopamine + tetani group depicted in
Fig. 1E). B, LTD by 50 Hz tetani
in the presence of 1S,3R-ACPD (Fig.
6A) was also blocked by bath application of
PD98059. Mean change of the EPSP slope measured 35-40 min after drug
washout-tetani was 0.6 ± 3.9% [n = 4, p < 0.002 vs
1S,3R-ACPD + tetani group (Fig.
6A)]. C, LTD by coactivation of
dopamine receptors and groups I and II mGluRs with
1S,3R-ACPD (Fig. 9A) is
blocked by PD98059. Mean change of the EPSP slope measured 35-40 min
after drug washout was 4.9 ± 5.8% (n = 6, p < 0.02 vs the group depicted in Fig.
9A). D, LTD by dopamine + 1S,3R-ACPD coapplication is also blocked
by postsynaptic injection of specific synthetic MAP-K substrate peptide
Ala-Pro-Arg-Thr-Pro-Gly-Gly-Arg-Arg (1 mM in electrode).
This peptide, when abundantly present, acts as a specific competitive
inhibitor against endogenous MAP-K substrates. Mean change of the EPSP
slope 35-40 min after drug washout was 8.4 ± 6.2%
[n = 5, p < 0.001 vs dopamine + 1S,3R-ACPD group (Fig.
9A)]. Thus, critical MAP-K activation for LTD induction
after coactivation of dopamine receptors and mGluRs occurs in
postsynaptic sites.
|
|
In a separate group of neurons (n = 5) (Fig.
10D), we tested postsynaptic locus of critical MAP-K
activation for induction of LTD by dopamine + 1S,3R-ACPD coapplication. This form of LTD was
chosen, because it does not require any presynaptic stimulation for its
induction (Fig. 9B) and because it is this form of LTD for
which we bioassayed MAP-K activity during induction (see next section).
We used synthetic MAP-K substrate peptide
Ala-Pro-Arg-Thr-Pro-Gly-Gly-Arg-Arg (Baron et al., 1996), which acts
under physiological conditions as a specific competitive inhibitor
against endogenous MAP-K substrates. The peptide was postsynaptically
injected through recording electrodes (1 mM in
electrodes). Diffusion was allowed for at least 45 min before the
application of dopamine and 1S,3R-ACPD. In five
of five cases, dopamine + 1S,3R-ACPD failed to
induce LTD under this condition. Mean changes of the EPSP slope
calculated from all five experiments are depicted in Figure
10D (8.4 ± 6.2% 35-40 min after drugs,
n = 5, p < 0.001 vs dopamine + 1S,3R-ACPD group). Thus, critical MAP-K
activation for LTD induction occurs in postsynaptic sites.
Synergistic-additive activation of MAP kinases by dopamine and
mGluR agonists
Provided with the above results, we decided to biochemically
isolate converging activation of MAP-Ks by dopamine receptors and
mGluRs in prefrontal tissue. Activation of MAP-Ks occurs through a dual
phosphorylation of threonine and tyrosine residues (Her et al., 1993).
We measured MAP-K activation by the use of antibody anti-active ERKs
recognizing only the dually phosphorylated active forms of ERK1 and
ERK2, after exposure of prefrontal tissue to the agonists and
antagonists of dopamine and mGlu receptors. As depicted in Figure
11A,B
(top traces), in the control condition, no phosphorylated
ERK1 (44 kDa) band was detected despite the presence of a modest level
of phosphorylated ERK2 (42 kDa). The top traces also show
that both dopamine (100 µM) and
1S,3R-ACPD (100 µM)
increase the phosphorylation of ERK2 (42 kDa) within 2 min after the
beginning of bath application. Coapplication of dopamine + 1S,3R-ACPD (a principal LTD condition) (Figs.
9A,B, 10C,D)
resulted in an apparent additive increase of the level of ERK2
phosphorylation. Similar patterns of ERK2 activity increases were seen
with the other mGluR agonists DHPG (100 µM) and
DCG IV (100 nM) (Fig.
11A,B). In the case of ERK1,
dopamine does not increase its phosphorylation, whereas
1S,3R-ACPD weakly increases it. Interestingly,
when dopamine and 1S,3R-ACPD are applied together (an LTD condition), an increase in the phosphorylation exceeds that
achieved by 1S,3R-ACPD alone, showing a clear
synergism (Fig. 11A,B). Again,
similar patterns of activity increases were obtained with DHPG and DCG
IV. As shown in the bottom traces of Figure 11A,B, the two phosphorylated bands
were demonstrated to correspond to p44/ERK1 and p42/ERK2, by the use of
antibody anti-ERK2, which recognizes nonphosphorylated p42/ERK2 and,
weakly, p44/ERK1.
View larger version (45K):
[in this window]
[in a new window]
|
Figure 11.
Dopamine and mGluR agonists additively
or synergistically activate MAP-Ks as detected with anti-active MAP-K
antibody. Slices were incubated at 28°C in buffer containing 1 µM bicuculline without other drugs
(CNT) or with dopamine (DA,
100 µM) or an mGluR agonist
(1S,3R-ACPD, 100 µM; DHPG,
100 µM; DCG IV, 100 nM) or both
for 2 or 5 min. Bicuculline itself did not change MAP-K activity (data
not shown). Equal amounts of lysates (50 µg) were resolved on a 10%
acrylamide gel. Activated MAP-Ks were detected with an antibody
anti-active MAP-Ks (anti-active ERKs) that recognizes dually
phosphorylated ERKs. After stripping, the immunoblot was reprobed with
polyclonal anti-ERK2 (see Materials and Methods). A,
B, Results with 2 and 5 min application, respectively.
Note that phosphorylated protein bands are always denser after dopamine
plus an mGluR agonist than either drug alone (see Results).
C, Quantification by scanning densitometry of the
autoradiogram of anti-active ERKs using NIH Image 1.6. The data are
representative of at least three independent experiments. For the ERK2
activity (2 and 5 min), every drug condition showed statistical
significance of at least p < 0.05 over control.
For the ERK1 activity (5 min), the increase seen in the presence of
dopamine and a given mGluR agonist was always significantly larger than
the increase seen in the presence of that mGluR agonist alone
(p < 0.05). The graph is plotted as
percentage changes relative to CNT levels for p42/ERK2, and raw
arbitrary numbers for p44/ERK1 because of the lack of p44/ERK1
phosphorylation in CNT.
|
|
In an additional experiment (n = 4), we determined
whether the group II mGluR antagonist MSOPPE affects MAP-K activity.
This experiment was performed for the following reason. Group II mGluRs are coupled negatively to cAMP (Tanabe et al., 1992, 1993). Therefore, their block might increase cAMP levels and lead to the activation of
MAP-Ks. If this is the case, then it would suggest that the blockade by
MSOPPE of LTD induction (Fig. 4A) may have resulted from a previous saturation of MAP-K activation rather than an inhibition of MAP-K activation through antagonism against synaptic stimulation of group II mGluRs. Prefrontal tissues were exposed to
MSOPPE (200 µM in the presence of bicuculline)
for 20 min, and ERK1 and ERK2 phosphorylations were determined. MSOPPE
did not increase MAP-K phosphorylation at all (data not shown),
rejecting the possibility that there is a tonic inhibition of MAP-K
activation by group II mGluRs. Rather, stimulation of group II mGluRs
activates MAP-Ks (Fig. 11, DCG IV results).
Quantification by scanning densitometry (Fig. 11C) shows
that in all drug conditions, maximal effect on the phosphorylation of
p44/ERK1 and p42/ERK2 was obtained at 5 min after drug application. Activation of p42/ERK2 with mGluR agonists
(1S,3R-ACPD, DHPG, or DCG IV) was approximately
fourfold over that of control condition (p < 0.05). With dopamine, activation of p42/ERK2 was approximately 2.5-fold
over control (p < 0.05). When dopamine and one
of the mGluR agonists were coapplied, the increase of p42/ERK2 reached approximately sixfold activation over control (p < 0.05). Activation of p44/ERK1 was undetectable in control and
dopamine conditions, as shown in Figure
11A,B. The mGluR agonists
stimulated p44/ERK1 phosphorylation. The combination of a mGluR agonist
with dopamine caused further increases of p44/ERK1 phosphorylation,
which are significantly different from the increases seen in the
presence of the mGluR agonist alone (p < 0.05).
We observed that the activation of MAP-Ks by these drugs declines to
basal level within 60 min after drug washout (data not shown).
In another set of experiments, we tested which subtype of dopamine
receptors is involved in the dopaminergic activation of MAP-Ks (Fig.
12). As shown in Figure
12A, dopamine (100 µM) increased p42/ERK2 phosphorylation, and also in this case the phosphorylation of
p44/ERK1. These increases were reduced by the presence of D1 antagonist
SCH23390 (1 µM) or D2 antagonist sulpiride (50 µM) and blocked by the co-presence of two
antagonists. Group results obtained from quantification by scanning
densitometry (Fig. 12B) revealed a synergistic effect
of D1 and D2 receptor activation on MAP-K phosphorylation. First,
dopamine increased p42/ERK2 phosphorylation more than twofold
(p < 0.005). The presence of either SCH23390 or
sulpiride was sufficient to significantly reduce the dopamine effect on
p42/ERK2 phosphorylation (p < 0.001 for the
dopamine + SCH23390 group and p < 0.05 for the
dopamine + sulpiride group, compared with dopamine group). Co-presence
of SCH23390 and sulpiride blocked the effect of dopamine on ERK2
phosphorylation (p < 001). Similar patterns of
the effects of dopamine and dopamine antagonists were seen for p42/ERK1
phosphorylation. These results show that sole activation of either D1
or D2 receptors by dopamine is insufficient to activate MAP-Ks; two
subtypes of dopamine receptors must be stimulated to bring about MAP-K
activation.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 12.
Dopamine D1 and D2 receptors synergistically
activate MAP-Ks as detected with anti-active MAP-K antibody. Methods
are similar to those depicted in Figure 11 except the use of D1
antagonist SCH23390 (1 µM) and D2 antagonist sulpiride
(50 µM). These antagonists were preincubated for 10 min
before dopamine (100 µM) was applied. In all results in
the figure, the duration of dopamine application was 2 min, but similar
results were obtained after 5 min application. A,
Phosphorylation bands of ERK1 and ERK2 after various conditions.
Control tissue showed a relatively dense band of ERK2 as in Figure 11
and also a light ERK1 band in this case. Dopamine increased
phosphorylation of both ERK1 and ERK2. Note that phosphorylation bands
are lighter in the presence of SCH23390 or sulpiride, and the band in
the presence of two antagonists is at control level. B,
Synergism between D1 and D2 receptors revealed by quantification by
scanning densitometry of the autoradiogram of anti-active ERKs using
NIH Image 1.6. Each group contains four observations. Dopamine
increased ERK1 and ERK2 phosphorylation more than twofold (ERK1,
p < 0.001; ERK2, p < 0.005).
This dopamine effect was highly significantly reduced by the presence
of the D1 antagonist SCH23390 (ERK1, p < 0.002;
ERK2, p < 0.001) or the D2 antagonist sulpiride
(ERK1, p < 0.002; ERK2, p < 0.05). Co-presence of SCH23390 and sulpiride blocked dopamine
phosphorylation of MAP-Ks (ERK1 and ERK2, p < 0.001). These results suggest that sole activation of either D1 or D2
receptors by dopamine is insufficient to bring about activation of
MAP-Ks. Two subtypes of dopamine receptors must be stimulated for MAP-K
activation. The graph is plotted as percentage changes relative to CNT
levels for both p42/ERK2 and p44/ERK1. For this purpose, control was
taken as 100 for ERK2 and 12.5 for ERK1, to reflect roughly the
ERK2/ERK1 densitometry proportion obtained by scanning.
|
|
| |
DISCUSSION |
Figure 13 schematically shows
possible mechanisms underlying LTD induction in layer I-II to layer V
pyramidal neuron glutamatergic synapses of rat prefrontal cortex, based
on the present results and those obtained in previous studies in this
laboratory. First (Fig. 13(a)), LTD induced by 50 Hz in the
presence of dopamine (depicted as a dopaminergic axon terminal) does
not require NMDA receptor activation (Otani et al., 1998b), consistent
with the fact that dopamine acutely depresses the NMDA component, as
well as the non-NMDA component, of synaptic transmission through
presynaptic or postsynaptic action, or both (Low-Tho et al., 1994;
Low-Tho, 1995; our unpublished observations). Second (Fig.
13(b)), dopamine, however, augments synaptic responses
during the LTD-inducing high-frequency drive to enhance postsynaptic
depolarization, which permits Ca2+ flow
through voltage-gated channels and facilitates LTD (Otani et al.,
1998b). At least L-type channels are not involved in the Ca2+ flow, because the L-channel blocker
nifedipine did not block LTD (our unpublished observation). The present
study showed that (Fig. 13(c)) LTD induction by 50 Hz
stimuli in the presence of dopamine is blockable by the application of
MCPG (groups I and II antagonist), AIDA (group I antagonist), or MSOPPE
(group II antagonist). Thus, for this LTD induction, concurrent
synaptic activation of group I and group II mGluRs during tetanus is
required. Furthermore, it was shown that
1S,3R-ACPD (groups I and II agonist), but not
DHPG (group I agonist), facilitates LTD induction by 50 Hz stimuli.
Moreover, coapplication of dopamine and
1S,3R-ACPD induced LTD without any presynaptic
electrical stimulation. Coapplication of dopamine and DHPG also induced
LTD, but in a somewhat less consistent fashion, and interestingly, the
potent group II agonist DCG IV by itself induced LTD in a postsynaptic
Ca2+-dependent manner. The important
involvement of group II mGluRs in LTD induction in prefrontal cortex
might explain why the recovery from the depression after sole
application of 1S,3R-ACPD is slower than that
after sole application of DHPG (Fig. 6B vs
7A).
View larger version (36K):
[in this window]
[in a new window]
|
Figure 13.
Schematic drawing of possible mechanisms for LTD
induction in prefrontal layer I-II to layer V pyramidal neuron
glutamatergic synapses. The coexistence of D1-like and D2-like dopamine
receptors and that of D2-like and glutamate in the same synapse are
still hypothetical. In classical protocol (Fig.
1E), LTD is induced by 50 Hz electrical
stimulation to the glutamatergic fibers in the presence of dopamine in
the bath (shown in the figure as a dopaminergic synaptic terminal).
(a) Dopamine alone acutely and reversibly depresses
low-frequency glutamatergic transmission, including the NMDA
receptor-mediated component (Law-Tho et al., 1994; Law-Tho, 1995; our
unpublished observation), by presynaptic or postsynaptic action, or
both, and accordingly, LTD induced by the classical protocol does not
require NMDA receptor activation (Otani et al., 1998b).
(b) During high-frequency (50 Hz) drive to glutamatergic
synapses, dopamine augments the synaptic responses and increases
postsynaptic depolarization (Otani et al., 1998). This effect of
dopamine serves as a critical factor for the NMDA-independent,
postsynaptic Ca2+-dependent induction of LTD (Otani
et al., 1998b). (c) In the present study, it was shown
that for this LTD induction, synaptic activation of both group I and
group II mGluRs is necessary (Figs. 2A,
3A, 4A). Moreover, coapplication
of dopamine and 1S,3R-ACPD consistently
induced LTD without tetanus or single synaptic stimuli, suggesting that
coactivation of dopamine receptors and the mGluRs is sufficient for LTD
induction (Fig. 9A,B). We
propose that a biochemical mechanism underlying this LTD induction is
converging postsynaptic activation of MAP-Ks (ERK1 and ERK2) by groups
I and II mGluRs and D1-like and D2-like dopamine receptors. Thus,
dopamine D1 and D2 receptors synergistically activate MAP-Ks (Fig. 12),
whereas group I mGluRs alone or group II mGluRs alone can activate
MAP-Ks (Fig. 11). A combined activation of the dopamine receptors and
mGluRs causes synergistic (ERK1) or additive (ERK2) increases of MAP-K
activity (Fig. 11). Second messenger pathways involved in this
converging MAP-K activation in prefrontal neurons (shown as pathways
i, ii, iii, and
iv) are yet to be demonstrated. However, the following
lines of evidence support our hypothesis. (i and
ii) Activation of MAP-Ks by PKC and PKA has been
demonstrated in various cell types including hippocampal cells (Nestler
and Greengard 1994; Cobb and Goldsmith, 1995; Robinson and Cobb, 1997;
Roberson et al., 1999). (iii) Lines of evidence suggest
that D2 receptors are coupled positively to phospholipase A2 and
production of arachidonic acid, which activates PKC (Piomelli et al.,
1991; Vial and Piomelli, 1995; Nilsson et al., 1998). There may be a
synergistic action between D1 and D2 receptors for arachidonic acid
production (Piomelli et al., 1991). (iv) It has been
reported that group II mGluR activation with DCG IV, as well as group I
mGluR activation with DHPG, stimulates the phospholipase D pathway,
which also leads to PKC activation (Klein et al., 1997).
|
|
Figure 13 also shows that a biochemical consequence of metabotropic
receptor cooperation (i.e., D1 and D2 receptors and groups I and II
mGluRs) is the postsynaptic converging activation of ERK1 and ERK2. Our
biochemical analyses showed that prefrontal MAP-Ks are activated by
dopamine, 1S,3R-ACPD, DHPG, and DCG IV. Importantly, when dopamine and one of the mGluR agonists were coapplied, there were synergistic (ERK1) or additive (ERK2) increases of MAP-Ks. Synergistic activation of MAP-Ks was also observed between
dopamine D1 and D2 receptors. In this case, blockade of either D1 or D2
receptors was sufficient to block dopamine activation of MAP-Ks. This
dopaminergic synergism is reminiscent of the synergistic action of D1
and D2 receptors in the production of arachidonic acid (Piomelli et
al., 1991), the potent PKC activator that can in turn activate MAP-Ks
(see below and Fig. 13 legend).
Consistent with the above results showing that MAP-Ks can be activated
through dopamine receptors and mGluRs, three forms of LTD reported in
this paper, i.e., LTD by 50 Hz stimuli in the presence of dopamine, LTD
by 50 Hz stimuli in the presence of 1S,3R-ACPD,
and LTD by coapplication of dopamine and
1S,3R-ACPD, were all blocked by bath application
of the specific ERK1 and ERK2 phosphorylation inhibitor PD98059.
Moreover, LTD by dopamine + 1S,3R-ACPD
coapplication, whose induction may be purely postsynaptic (Fig.
9B), was indeed blocked by a previous postsynaptic
inhibition of MAP-K-mediated phosphorylation with the specific
synthetic substrate peptide, showing that the critical converging
activation of MAP-Ks takes place in postsynaptic sites. The involvement
of MAP-Ks in synaptic plasticity is in line with other results obtained in hippocampus (Baron et al., 1996; English and Sweatt, 1996; Coogan et
al., 1999).
In this paper, we did not investigate the question regarding which
second messengers are involved in LTD and MAP-K activation. However,
the following lines of evidence support our hypotheses depicted in
Figure 13 (shown as pathways i, ii,
iii, and iv). First, it is well known that
dopamine D1 receptors are positively coupled to the adenylate
cyclase-cAMP-PKA pathway (Jaber et al., 1996) and group I mGluRs are
coupled to the phospholipase C-diacylglycerol-PKC pathway (Abe et
al., 1992; Joly et al., 1995). These two major protein kinases activate
MAP-Ks in various cell types including hippocampal neurons (pathways
i and ii) (Nestler and Greengard, 1994; Cobb and
Goldsmith, 1995; Robinson and Cobb, 1997; Roberson et al., 1999).
Dopamine D2 receptors are classically known to downregulate the PKA
pathway (Jaber et al., 1996), but it is also known that D2 receptors
are positively coupled to phospholipase A2, whose activation produces
arachidonic acid, a potent PKC activator (pathway iii)
(Piomelli et al., 1991; Vial and Piomelli, 1995; Nilsson et al., 1998).
In this respect, D1 receptors might act with D2 receptors and
synergistically produce arachidonic acid (Piomelli et al., 1991), to
bring about at least partially the synergistic activation of MAP-Ks
(Fig. 12). Similar to D2 receptors, group II mGluRs are classically
known to be negatively coupled to cAMP (Tanabe et al., 1992, 1993).
Although this appears to be the case for presynaptic group II receptors
(see Figs. 5 and 8A for acute effects of MSOPPE and
DCG IV), postsynaptic group II mGluRs might be also positively coupled
to phospholipase D (Klein et al., 1997), whose activation leads to PKC
activation (pathway iv) (Tanaka and Nishizuka, 1994).
Postsynaptic localization of
Ca2+-dependent processes involving group
II mGluRs was suggested by our result that DCG IV alone
postsynaptically induces LTD (Fig. 8A,B).
In some neurons treated with the group II antagonist MSOPPE, 50 Hz
tetanic stimuli induced large STP (three of nine) or an STP followed by
some degree of lasting potentiation (16%, one of nine). Analyses of
synaptic responses in the presence of MSOPPE revealed that the drug
enhances postsynaptic activity during tetanus. It is likely that this
effect of MSOPPE on synaptic responses, probably attributable to its
presynaptic action, underlies the plasticity induction in the MSOPPE
condition. This notion further suggests that under normal conditions,
presynaptic activation of group II mGluRs by released glutamate and a
resulting downregulation of glutamate release inhibit LTP induction
(cf. Huang et al., 1997). It is important, however, to note that the
abnormal enhancement of synaptic responses during tetanus by MSOPPE is
not a mechanism by which MSOPPE inhibited dopaminergic facilitation of
LTD induction. This is because dopamine itself enhances synaptic
activity during tetanus (Otani et al., 1998b), which is sufficient to
occlude the effect of MSOPPE (see Results).
Modification of prefrontal glutamatergic transmission by dopamine
appears critical for normal cognitive function. For example, the
spatial specificity in working memory-related discharge of layer III
neurons in monkey dorsolateral prefrontal cortex depends on a normal
functioning of local D1 receptors (Williams and Goldman-Rakic, 1995).
In fact, injection of D1 antagonists to dorsolateral prefrontal cortex
in monkeys (Sawaguchi and Goldman-Rakic, 1994), or abnormal hyperactivation of D1 receptors in prefrontal area in rats (Zahrt et
al., 1997), disrupts working memory performance. Furthermore, the
psychotomimetic NMDA antagonists ketamine and phencyclidine (PCP)
increase dopamine outflow in rat prefrontal cortex (Nishijima et al.,
1994; Adams and Moghaddam, 1998) and impair working memory in rats
(Moghaddam et al., 1997; Moghaddam and Adams, 1998). Importantly, PCP
was also found to increase glutamate outflow in rat prefrontal cortex
(Moghaddam and Adams, 1998), and a pharmacological block of this
glutamate increase, even when dopamine level is still high, ameliorates
the PCP-induced impairment of working memory (Adams and Moghaddam,
1998; Moghaddam and Adams, 1998), confirming that abnormality in
glutamatergic transmission is probably the direct cause of cognitive
impairment. It is yet to be demonstrated whether synaptic depression of
prefrontal glutamatergic transmission is related to cognitive function.
However, mechanistically, LTD in prefrontal cortex is readily induced
when glutamatergic synapses are stimulated simultaneously with
dopamine receptors. Thus, under physiological or pathological
conditions, LTD might result from a coincident transmission at
glutamatergic and dopaminergic synapses located on the same neuron. The
present study revealed that for this LTD induction, cooperation between
groups I and II mGluRs and dopamine receptors serves as a critical mechanism.
| |
FOOTNOTES |
Received June 30, 1999; revised Aug. 25, 1999; accepted Sept. 1, 1999.
This work was financially supported by Biotech (CT96-0049). We thank O. Blond for his contribution to some of the experiments described in this paper.
Correspondence should be addressed to Dr. Satoru Otani, Laboratoire de
Neurobiologie et Neuropharmacologie du Développement, Institut
des Neurosciences case8, Université de Paris VI, Building B, 6th
floor, 7 quai Saint Bernard, 75005 Paris, France. E-mail: satoru.otani{at}snv.jussieu.fr.
| |
REFERENCES |
-
Abe T,
Sugihara H,
Nawa H,
Shigemoto R,
Mizuno N,
Nakanishi S
(1992)
Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phophate/Ca2+ signal transduction.
J Biol Chem
267:13361-13368[Abstract/Free Full Text].
-
Adams B,
Moghaddam B
(1998)
Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine.
J Neurosci
18:5545-5554[Abstract/Free Full Text].
-
Alessi DR,
Cuenda A,
Cohen P,
Dudley DT,
Saltiel AR
(1995)
PD98059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.
J Biol Chem
270:27489-27494[Abstract/Free Full Text].
-
Aniksztejn L,
Otani S,
Ben-Ari Y
(1992)
Quisqualate metabotropic receptors modulate NMDA currents and facilitate induction of long-term potentiation through protein kinase C.
Eur J Neurosci
4:500-505[Web of Science][Medline].
-
Barchas JD,
Faull KF,
Quinn B,
Elliott GR
(1994)
Biochemical aspects of the psychotic disorders.
In: Basic neurochemistry, Ed 5 (Siegel GJ,
Agranoff BW,
Albers RW,
Molinoff PB,
eds), pp 959-1001. New York: Raven.
-
Baron C,
Benes C,
Huynh VT,
Fagard R,
Roisin MP
(1996)
Potassium chloride pulse enhances MAP kinase activity in rat hippocampal slices.
J Neurochem
66:1005-1010[Web of Science][Medline].
-
Bashir ZI,
Bortolotto ZA,
Davies CH,
Berretta N,
Irving AJ,
Seal AJ,
Henley JM,
Jane DE,
Watkins JC,
Collingridge GL
(1993)
Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors.
Nature
363:347-350[Medline].
-
Bear MF,
Abraham WC
(1996)
Long-term depression in hippocampus.
Annu Rev Neurosci
19:437-462[Web of Science][Medline].
-
Bergson C,
Mrzljak L,
Smiley JF,
Pappy M,
Levenson R,
Goldman-Rakic PS
(1995)
Regional, cellular, and subcellular variations in the distributions of D1 and D5 dopamine receptors in primate brain.
J Neurosci
15:7821-7836[Abstract].
-
Bliss TVP,
Collingridge GL
(1993)
A synaptic model of memory: long-term potentiation in the hippocampus.
Nature
361:31-39[Medline].
-
Brabet I,
Mary S,
Bockaert J,
Pin J-P
(1995)
Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses.
Neuropharmacology
34:895-903[Web of Science][Medline].
-
Bradford M
(1976)
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
Anal Biochem
72:248-254[Web of Science][Medline].
-
Bradley SR,
Levey AI,
Hersch SM,
Conn PJ
(1996)
Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies.
J Neurosci
16:2044-2056[Abstract/Free Full Text].
-
Cobb MH,
Goldsmith EJ
(1995)
How MAP kinases are regulated.
J Biol Chem
270:14843-14846[Free Full Text].
-
Coogan AN,
O'Leary DM,
O'Connor JJ
(1999)
P42/44 MAP kinase inhibitor PD98059 attenuates multiple forms of synaptic plasticity in rat dentate gyrus in vitro.
J Neurophysiol
81:103-110[Abstract/Free Full Text].
-
Cohen P
(1997)
The search for physiological substrates of MAP and SAP kinases in mammalian cells.
Trends Cell Biol
7:353-361.
-
Conn PJ,
Pin J-P
(1997)
Pharmacology and functions of metabotropic glutamate receptors.
Annu Rev Pharmacol Toxicol
37:205-237[Web of Science][Medline].
-
Dudley DT,
Pang L,
Decker SJ,
Bridges AJ,
Saltiel AR
(1995)
A synthetic inhibitor of the mitogen-activated PKC cascade.
Proc Natl Acad Sci USA
92:7686-7689[Abstract/Free Full Text].
-
English JD,
Sweatt JD
(1996)
Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation.
J Biol Chem
271:24329-24332[Abstract/Free Full Text].
-
Fotuhi M,
Sharp AH,
Glatt CE,
Hwang PM,
von Krosigk M,
Snyder H,
Dawson TM
(1993)
Differential localization of phosphoinositide-linked metabotropic glutamate receptor (mGluR1) and the inositol 1,4,5-trisphosphate receptor in rat brain.
J Neurosci
13:2001-2012[Abstract].
-
Gereau IV RW,
Conn PJ
(1995)
Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1.
J Neurosci
15:6879-6889[Abstract/Free Full Text].
-
Glowinski J,
Tassin JP,
Thierry AM
(1984)
The mesocortico-prefrontal dopaminergic neurons.
Trends Neurosci
7:415-418.
-
Goldman-Rakic P
(1995)
Cellular basis of working memory.
Neuron
14:477-485[Web of Science][Medline].
-
Her JH,
Lakhani S,
Zu K,
Vila J,
Dent P,
Sturgill TW,
Weber MJ
(1993)
Dual phosphorylation and autophosphorylation in mitogen-activated protein (MAP) kinase activation.
Biochem J
296:25-31.
-
Hirsch JC,
Crepel F
(1990)
Use-dependent changes in synaptic efficacy in rat prefrontal neurons in vitro.
J Physiol (Lond)
427:31-49[Abstract/Free Full Text].
-
Huang L-Q,
Rowan MJ,
Anwyl R
(1997)
mGluR II agonist inhibition of LTP induction, and mGluR II antagonist inhibition of LTD induction, in the dentate gyrus in vitro.
NeuroReport
8:687-693[Web of Science][Medline].
-
Ishida M,
Saitoh T,
Shimamoto K,
Ohfune Y,
Shinozaki H
(1993)
A novel metabotropic glutamate receptor agonist: marked depression of monosynaptic excitation in the newborn rat isolated spinal cord.
Br J Pharmacol
109:1169-1177[Web of Science][Medline].
-
Iversen SD
(1995)
Interactions between excitatory amino acids and dopamine systems in the forebrain: implications for schizophrenia and Parkinson's disease.
Behav Pharmacol
6:478-491[Web of Science][Medline].
-
Jaber M,
Robinson SW,
Missale C,
Caron MG
(1996)
Dopamine receptors and brain function.
Neuropharmacology
35:1503-1519[Web of Science][Medline].
-
Jin X,
Daw NW
(1998)
The group III metabotropic glutamate receptor agonist, l-AP4, reduces EPSPs in some layers of rat visual cortex.
Brain Res
797:218-224[Web of Science][Medline].
-
Joly C,
Gomeza J,
Brabet I,
Curry K,
Bockaert J,
Pin J-P
(1995)
Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison with mGluR1.
J Neurosci
15:3970-3981[Abstract].
-
Kato N
(1993)
Dependence of long-term depression on postsynaptic metabotropic glutamate receptors in visual cortex.
Proc Natl Acad Sci USA
90:3650-3654[Abstract/Free Full Text].
-
Klein J,
Iovino M,
Vakil M,
Shinozaki H,
Löffelholz K
(1997)
Ontogenetic and pharmacological studies on metabotropic glutamate receptors coupled to phospholipase D activation.
Neuropharmacology
36:305-311[Web of Science][Medline].
-
Kolb B
(1984)
Functions of the frontal cortex of the rat: a comparative review.
Brain Res Rev
8:65-98.
-
Kuroda M,
Murakami K,
Igarashi H,
Okada A
(1996)
The convergence of axon terminals from the mediodorsal thalamic nucleus and ventral tegmental area on pyramidal cells in layer V of the rat prelimbic cortex.
Eur J Neurosci
8:1340-1349[Web of Science][Medline].
-
Law-Tho D
(1995)
Etude in vitro des effets des catecholamines (dopamine et noradrenaline) sur la transmission et la plasticite synaptiques dans le cortex prefrontal du rat.
In: PhD thesis Université de Paris-Sud.
-
Law-Tho D,
Hirsch JC,
Crepel F
(1994)
Dopamine modulation of synaptic transmission in rat prefrontal cortex: an in vitro electrophysiological study.
Neurosci Res
21:151-160[Web of Science][Medline].
-
Law-Tho D,
Desce JM,
Crepel F
(1995)
Dopamine favours the emergence of long-term depression versus long-term potentiation in slices of rat prefrontal cortex.
Neurosci Lett
188:125-128[Web of Science][Medline].
-
Manahan-Vaughan D,
Braunewell K-H,
Reymann KG
(1998)
Subtype-specific involvement of metabotropic glutamate receptors in two forms of long-term potentiation in the dentate gyrus of freely moving rats.
Neuroscience
86:709-721[Web of Science][Medline].
-
Moghaddam B,
Adams BW
(1998)
Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats.
Science
281:1349-1352[Abstract/Free Full Text].
-
Moghaddam B,
Adams BW,
Verma A,
Daly D
(1997)
Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex.
J Neurosci
17:2921-2927[Abstract/Free Full Text].
-
Moroni F,
Lombardi G,
Thomsen C,
Leonardi P,
Attucci S,
Peruginelli F,
Albani-Torregrossa S,
Pellegrini-Giampietro DE,
Luneia R,
Pellicciari R
(1997)
Pharmacological characterization of 1-aminoindan-1,5-ducarboxylic acid, AIDA, a potent mGluR1 antagonist.
J Pharmacol Exp Ther
281:721-729[Abstract/Free Full Text].
-
Morris SH,
Keelan J,
Patterson L,
Duchen MR,
Bindman LJ
(1998)
Group I metabotropic glutamate receptor (mGluR) agonists raise intracellular [Ca++] in medial frontal cortical neurons of the rat.
Soc Neurosci Abstr
24:2024.
-
Nestler EJ,
Greengard P
(1994)
Protein phosphorylation and the regulation of neuronal function.
In: Basic neurochemistry (Siegel GJ,
Agranoff BW,
Albers RW,
Molinoff PB,
eds), pp 449-474. New York: Raven.
-
Nicoletti F,
Bruno V,
Copani A,
Casabona G,
Knöpfel T
(1996)
Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders?
Trends Neurosci
19:267-271[Web of Science][Medline].
-
Nilsson CL,
Hellstrand M,
Ekman A,
Eriksson E
(1998)
Direct dopamine D2-receptor-mediated modulation of arachidonic acid release in transfected CHO cells without the concomitant administration of a Ca2+-mobilizing agent.
Br J Pharmacol
124:1651-1658[Web of Science][Medline].
-
Nishijima K,
Kashiwa A,
Nishikawa T
(1994)
Preferential stimulation of extracellular release of dopamine in rat frontal cortex to striatum following competitive inhibition of the N-methyl-D-aspartate receptor.
J Neurochem
63:375-378[Medline].
-
Okubo Y,
Suhara T,
Suzuki K,
Kobayashi K,
Inoue O,
Terasaki O,
Someya Y,
Sassa T,
Sudo Y,
Matsushima E,
Iyo M,
Tateno Y,
Toru M
(1997)
Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET.
Nature
385:634-636[Medline].
-
Oliet S,
Malenka RC,
Nicoll RA
(1997)
Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells.
Neuron
18:969-982[Web of Science][Medline].
-
Otani S,
Ben-Ari Y
(1993)
Biochemical correlates of long-term potentiation in hippocampal synapses.
Int Rev Neurobiol
35:1-41[Web of Science][Medline].
-
Otani S,
Connor JA
(1998)
Requirement of rapid Ca2+ entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus.
J Physiol (Lond)
511:761-770[Abstract/Free Full Text].
-
Otani S,
Auclair N,
Desce J-M,
Crépel F
(1998a)
Dopaminergic receptors and metabotropic glutamate receptors cooperate to induce LTD in rat prefrontal glutamatergic synapses.
Soc Neurosci Abstr
24:2024.
-
Otani S,
Blond O,
Desce J-M,
Crépel F
(1998b)
Dopamine facilitates long-term depression of glutamatergic transmission in rat prefrontal cortex.
Neuroscience
85:669-676[Web of Science][Medline].
-
Otani S,
Desce J-M,
Blond O,
Crépel F
(1998c)
Interaction between dopamine receptors and group II mGluRs for LTD induction in rat prefrontal cortex.
J Physiol (Lond)
507:26P.
-
Petralia RS,
Wang Y-X,
Niedzielski AS,
Wenthold RJ
(1996)
The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations.
Neuroscience
71:949-976[Web of Science][Medline].
-
Piomelli D,
Pilon C,
Giros B,
Sokoloff P,
Martres MP,
Schwartz JC
(1991)
Dopamine activation of the arachidonic acid cascade as a basis for D1/D2 receptor synergism.
Nature
353:164-167[Medline].
-
Roberson ED,
English JD,
Adams JP,
Selcher JC,
Kondratick C,
Sweatt JD
(1999)
The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus.
J Neurosci
19:4337-4348[Abstract/Free Full Text].
-
Robinson MJ,
Cobb MH
(1997)
Mitogen-activated protein kinase pathways.
Curr Opin Cell Biol
9:180-186[Web of Science][Medline].
-
Romano C,
Sesma MA,
McDonald CT,
O'Malley K,
van del Pol AN,
Olney JW
(1995)
Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain.
J Comp Neurol
355:455-469[Web of Science][Medline].
-
Sawaguchi T,
Goldman-Rakic PS
(1994)
The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of Rhesus monkeys performing an oculomotor delayed-response task.
J Neurophysiol
71:515-528[Abstract/Free Full Text].
-
Sekiyama N,
Hayashi Y,
Nakanishi S,
Jane DE,
Tse H-W,
Birse EF,
Watkins JC
(1996)
Structure-acticity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes.
Br J Pharmacol
117:1493-1503[Web of Science][Medline].
-
Simon H,
Scatton B,
Le Moal M
(1980)
Dopaminergic A10 neurons are involved in cognitive functions.
Nature
286:150-151[Medline].
-
Smiley JF,
Levey AL,
Ciliax BJ,
Goldman-Rakic PS
(1994)
D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines.
Proc Natl Acad Sci USA
91:5720-5724[Abstract/Free Full Text].
-
Tanabe Y,
Masu M,
Ishii T,
Shigemoto R,
Nakanishi S
(1992)
A family of metabotropic glutamate receptors.
Neuron
8:169-179[Web of Science][Medline].
-
Tanabe Y,
Nomura A,
Masu M,
Shigemoto R,
Mizuno N,
Nakanishi S
(1993)
Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4.
J Neurosci
13:1372-1378[Abstract].
-
Tanaka C,
Nishizuka Y
(1994)
The protein kinase C family for neuronal signaling.
Annu Rev Neurosci
17:551-567[Web of Science][Medline].
-
Thomas NK,
Jane DE,
Tse H-W,
Watkins JC
(1996)
-Methyl derivatives of serine-O-phosphate as novel, selective competitive metabotropic glutamate receptor antagonists.
Neuropharmacology
35:637-642[Web of Science][Medline].
-
Towbin H,
Staehelin T,
Gordon J
(1979)
Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications.
Proc Natl Acad Sci USA
76:4350-4354[Abstract/Free Full Text].
-
Vial D,
Piomelli D
(1995)
Dopamine D2 receptors potentiate arachidonate release via activation of cytosolic, arachidonate-specific phospholipase A2.
J Neurochem
64:2765-2772[Web of Science][Medline].
-
Vickery RM,
Morris SH,
Bindman LJ
(1997)
Metabotropic glutamate receptors are involved in long-term potentiation in isolated slices of rat medial frontal cortex.
J Neurophysiol
78:3039-3046[Abstract/Free Full Text].
-
Williams GV,
Goldman-Rakic PS
(1995)
Modulation of memory fields by dopamine D1 receptors in prefrontal cortex.
Nature
376:572-575[Medline].
-
Wilsch VW,
Pidoplichko VI,
Opitz T,
Shinozaki H,
Reymann KG
(1994)
Metabotropic glutamate receptor agonist DCG-IV as NMDA receptor agonist in immature rat hippocampal neurons.
Eur J Pharmacol
262:287-291[Web of Science][Medline].
-
Zahrt J,
Taylor JR,
Mathew RG,
Arnsten AFT
(1997)
Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance.
J Neurosci
17:8528-8535[Abstract/Free Full Text].
Copyright © 1999 Society for Neuroscience 0270-6474/99/19229788-15$05.00/0
This article has been cited by other articles:
|
|
|
|
 
B. Kolomiets, A. Marzo, J. Caboche, P. Vanhoutte, and S. Otani
Background Dopamine Concentration Dependently Facilitates Long-term Potentiation in Rat Prefrontal Cortex through Postsynaptic Activation of Extracellular Signal-Regulated Kinases
Cereb Cortex,
March 12, 2009;
(2009)
bhp047v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Zhong, W. Liu, Z. Gu, and Z. Yan
Serotonin facilitates long-term depression induction in prefrontal cortex via p38 MAPK/Rab5-mediated enhancement of AMPA receptor internalization
J. Physiol.,
September 15, 2008;
586(18):
4465 - 4479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Scheiderer, C. C. Smith, E. McCutchen, P. A. McCoy, E. E. Thacker, K. Kolasa, L. E. Dobrunz, and L. L. McMahon
Coactivation of M1 Muscarinic and {alpha}1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3-CA1 Synapses in Rat Hippocampus
J. Neurosci.,
May 14, 2008;
28(20):
5350 - 5358.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-C. Huang, P.-C. Yang, H.-J. Lin, and K.-S. Hsu
Repeated Cocaine Administration Impairs Group II Metabotropic Glutamate Receptor-Mediated Long-Term Depression in Rat Medial Prefrontal Cortex
J. Neurosci.,
March 14, 2007;
27(11):
2958 - 2968.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Matsuda, A. Marzo, and S. Otani
The presence of background dopamine signal converts long-term synaptic depression to potentiation in rat prefrontal cortex.
J. Neurosci.,
May 3, 2006;
26(18):
4803 - 4810.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Wei, K. I. Vadakkan, H. Toyoda, L.-J. Wu, M.-G. Zhao, H. Xu, F. W.F. Shum, Y. H. Jia, and M. Zhuo
Calcium Calmodulin-Stimulated Adenylyl Cyclases Contribute to Activation of Extracellular Signal-Regulated Kinase in Spinal Dorsal Horn Neurons in Adult Rats and Mice
J. Neurosci.,
January 18, 2006;
26(3):
851 - 861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-Y. Choi, J. Chang, B. Jiang, G.-H. Seol, S.-S. Min, J.-S. Han, H.-S. Shin, M. Gallagher, and A. Kirkwood
Multiple Receptors Coupled to Phospholipase C Gate Long-Term Depression in Visual Cortex
J. Neurosci.,
December 7, 2005;
25(49):
11433 - 11443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Navakkode, S. Sajikumar, and J. U. Frey
Mitogen-Activated Protein Kinase-Mediated Reinforcement of Hippocampal Early Long-Term Depression by the Type IV-Specific Phosphodiesterase Inhibitor Rolipram and Its Effect on Synaptic Tagging
J. Neurosci.,
November 16, 2005;
25(46):
10664 - 10670.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Sun, Y. Zhao, and M. E. Wolf
Dopamine Receptor Stimulation Modulates AMPA Receptor Synaptic Insertion in Prefrontal Cortex Neurons
J. Neurosci.,
August 10, 2005;
25(32):
7342 - 7351.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Kawasaki, T. Kohno, Z.-Y. Zhuang, G. J. Brenner, H. Wang, C. Van Der Meer, K. Befort, C. J. Woolf, and R.-R. Ji
Ionotropic and Metabotropic Receptors, Protein Kinase A, Protein Kinase C, and Src Contribute to C-Fiber-Induced ERK Activation and cAMP Response Element-Binding Protein Phosphorylation in Dorsal Horn Neurons, Leading to Central Sensitization
J. Neurosci.,
September 22, 2004;
24(38):
8310 - 8321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Manunta and J.-M. Edeline
Noradrenergic Induction of Selective Plasticity in the Frequency Tuning of Auditory Cortex Neurons
J Neurophysiol,
September 1, 2004;
92(3):
1445 - 1463.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hugues, O. Deschaux, and R. Garcia
Postextinction Infusion of a Mitogen-Activated Protein Kinase Inhibitor Into the Medial Prefrontal Cortex Impairs Memory of the Extinction of Conditioned Fear
Learn. Mem.,
September 1, 2004;
11(5):
540 - 543.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Rancillac and F. Crepel
Synapses between parallel fibres and stellate cells express long-term changes in synaptic efficacy in rat cerebellum
J. Physiol.,
February 1, 2004;
554(3):
707 - 720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Otani, H. Daniel, M.-P. Roisin, and F. Crepel
Dopaminergic Modulation of Long-term Synaptic Plasticity in Rat Prefrontal Neurons
Cereb Cortex,
November 1, 2003;
13(11):
1251 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Paquet and Y. Smith
Group I Metabotropic Glutamate Receptors in the Monkey Striatum: Subsynaptic Association with Glutamatergic and Dopaminergic Afferents
J. Neurosci.,
August 20, 2003;
23(20):
7659 - 7669.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bao, V. T. Chan, L. I. Zhang, and M. M. Merzenich
Suppression of cortical representation through backward conditioning
PNAS,
February 4, 2003;
100(3):
1405 - 1408.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Saulle, D. Centonze, A. B. Martin, R. Moratalla, G. Bernardi, and P. Calabresi
Endogenous Dopamine Amplifies Ischemic Long-Term Potentiation via D1 Receptors
Stroke,
December 1, 2002;
33(12):
2978 - 2984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Gubellini, B. Picconi, M. Bari, N. Battista, P. Calabresi, D. Centonze, G. Bernardi, A. Finazzi-Agro, and M. Maccarrone
Experimental Parkinsonism Alters Endocannabinoid Degradation: Implications for Striatal Glutamatergic Transmission
J. Neurosci.,
August 15, 2002;
22(16):
6900 - 6907.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Yang and R. W. Gereau IV
Peripheral Group II Metabotropic Glutamate Receptors (mGluR2/3) Regulate Prostaglandin E2-Mediated Sensitization of Capsaicin Responses and Thermal Nociception
J. Neurosci.,
August 1, 2002;
22(15):
6388 - 6393.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Wolf
Addiction: Making the Connection Between Behavioral Changes and Neuronal Plasticity in Specific Pathways
Mol. Interv.,
June 1, 2002;
2(3):
146 - 157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Robbe, G. Alonso, S. Chaumont, J. Bockaert, and O. J. Manzoni
Role of P/Q-Ca2+ Channels in Metabotropic Glutamate Receptor 2/3-Dependent Presynaptic Long-Term Depression at Nucleus Accumbens Synapses
J. Neurosci.,
June 1, 2002;
22(11):
4346 - 4356.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Otani, H. Daniel, M. Takita, and F. Crepel
Long-Term Depression Induced by Postsynaptic Group II Metabotropic Glutamate Receptors Linked to Phospholipase C and Intracellular Calcium Rises in Rat Prefrontal Cortex
J. Neurosci.,
May 1, 2002;
22(9):
3434 - 3444.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Renger, K. N. Hartman, Y. Tsuchimoto, M. Yokoi, S. Nakanishi, and T. K. Hensch
Experience-dependent plasticity without long-term depression by type 2 metabotropic glutamate receptors in developing visual cortex
PNAS,
January 22, 2002;
99(2):
1041 - 1046.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Calabresi, E. Saulle, G. A. Marfia, D. Centonze, R. Mulloy, B. Picconi, R. A. Hipskind, F. Conquet, and G. Bernardi
Activation of Metabotropic Glutamate Receptor Subtype 1/Protein Kinase C/Mitogen-Activated Protein Kinase Pathway Is Required for Postischemic Long-Term Potentiation in the Striatum
Mol. Pharmacol.,
October 1, 2001;
60(4):
808 - 815.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Schultz
Book Review: Reward Signaling by Dopamine Neurons
Neuroscientist,
August 1, 2001;
7(4):
293 - 302.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. Calabresi, P. Gubellini, B. Picconi, D. Centonze, A. Pisani, P. Bonsi, P. Greengard, R. A. Hipskind, E. Borrelli, and G. Bernardi
Inhibition of Mitochondrial Complex II Induces a Long-Term Potentiation of NMDA-Mediated Synaptic Excitation in the Striatum Requiring Endogenous Dopamine
J. Neurosci.,
July 15, 2001;
21(14):
5110 - 5120.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Oak, N. Lavine, and H. H. M. Van Tol
Dopamine D4 and D2L Receptor Stimulation of the Mitogen-Activated Protein Kinase Pathway Is Dependent on trans-Activation of the Platelet-Derived Growth Factor Receptor
Mol. Pharmacol.,
July 1, 2001;
60(1):
92 - 103.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
W.-J. Gao, L. S. Krimer, and P. S. Goldman-Rakic
Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits
PNAS,
December 22, 2000;
(2000)
11524298.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. A. Henze, G. R. Gonzalez-Burgos, N. N. Urban, D. A. Lewis, and G. Barrionuevo
Dopamine Increases Excitability of Pyramidal Neurons in Primate Prefrontal Cortex
J Neurophysiol,
December 1, 2000;
84(6):
2799 - 2809.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. E. Berman, S. Hazvi, V. Neduva, and Y. Dudai
The Role of Identified Neurotransmitter Systems in the Response of Insular Cortex to Unfamiliar Taste: Activation of ERK1-2 and Formation of a Memory Trace
J. Neurosci.,
September 15, 2000;
20(18):
7017 - 7023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Watabe, P. A. Zaki, and T. J. O'Dell
Coactivation of beta -Adrenergic and Cholinergic Receptors Enhances the Induction of Long-Term Potentiation and Synergistically Activates Mitogen-Activated Protein Kinase in the Hippocampal CA1 Region
J. Neurosci.,
August 15, 2000;
20(16):
5924 - 5931.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-J. Gao, L. S. Krimer, and P. S. Goldman-Rakic
Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits
PNAS,
January 2, 2001;
98(1):
295 - 300.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
