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* Howard Hughes Medical Institute and Molecular and Computational
Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines
Road, La Jolla, CA 92037; Contributed by Charles F. Stevens, October 30, 2000
Dopamine acts mainly through the D1/D5 receptor in the prefrontal
cortex (PFC) to modulate neural activity and behaviors associated with
working memory. To understand the mechanism of this effect, we examined
the modulation of excitatory synaptic inputs onto layer V PFC pyramidal
neurons by D1/D5 receptor stimulation. D1/D5 agonists increased the
size of N-methyl-D-aspartate (NMDA)
component of excitatory postsynaptic currents (EPSCs) through a
postsynaptic mechanism. In contrast, D1/D5 agonists caused a slight
reduction in the size of the non-NMDA component of EPSCs through a
small decrease in release probability. With 20 Hz synaptic trains, we found that the D1/D5 agonists increased depolarization of summating the NMDA component of excitatory postsynaptic potential (EPSP). By
increasing the NMDA component of EPSCs, yet slightly reducing release,
D1/D5 receptor activation selectively enhanced sustained synaptic
inputs and equalized the sizes of EPSPs in a 20-Hz train.
Dopamine regulates working
memory processes involving the prefrontal cortex (PFC). Dopamine levels
are elevated in the PFC during performance of working memory tasks (1),
and task performance is generally modulated by the D1, but not D2,
class of dopamine receptors (2-5). Dopamine, acting on D1 receptors,
also significantly increases delay and response-related activity of PFC
neurons during working memory tasks while only moderately augmenting
background activity (2, 3, 6, 7). The link between the biophysical mechanisms of D1-mediated modulation and their functional consequences has not, however, been established.
Dopaminergic and glutamatergic axon terminals form "synaptic
triads" on the postsynaptic dendrites of deep layer prefrontal cortex pyramidal neurons and dopamine contacts are found on somatic and
dendritic regions of pyramidal and nonpyramidal neurons in the rat PFC,
especially in the deeper laminae (8-10). Glutamatergic afferents from
the hippocampus and dopaminergic terminals are, moreover, in direct
apposition to one another in the PFC, suggesting a presynaptic site of
modulation (8). The few physiological studies available to date
indicate that dopamine is capable of altering excitatory synaptic
responses in the PFC, although the mode of action is not known
(11-15).
Computer models have suggested that the
N-methyl-D-aspartate (NMDA) component
of synaptic currents are critical for stabilizing sustained activity;
large non-NMDA components of synaptic currents, in contrast, render
delay-type activity less robust to interfering inputs and noise
(16-20). Therefore, understanding how D1 receptor activation affects
synaptic responses in PFC neurons is critical for understanding the
functional neuromodulation of sustained activity patterns underlying
working memory processes within the PFC.
Here, we characterize the neuromodulatory effects of D1 agonists
on glutamatergic inputs to layer V PFC neurons. D1 receptor activation
increased NMDA responses while slightly reducing non-NMDA responses. As
a result, D1 agonists tended to equalize the response to a 20-Hz input
train, a typical frequency observed during the delay period of working
memory tasks (2, 3, 6, 7, 21-24). Exactly these modulatory effects
enhanced sustained activity during delay periods in networks of
simulated PFC neurons (17).
The brains of Sprague-Dawley or Long-Evans rats (14-20 days;
Salk Colony) were rapidly dissected and immersed for 1 min in cold
(4°C) oxygenated artificial cerebrospinal fluid (ACSF) with the
following components (in mM): KCl (2.5),
NaH2PO4 (1.25),
NaHCO3 (25), CaCl2 (0.5),
MgCl2 (6), dextrose (25), ascorbic acid (1.3),
pyruvic acid (2.4), NaCl (125). Choline (110) or sucrose (200) was
routinely substituted for NaCl to prevent excitotoxic damage resulting
from severing of axons during slicing. After cutting, 300-µm slices
containing the prelimbic/infralimbic region of the PFC were
transferred to ACSF containing (in mM): NaCl (126), KCl (3),
NaHCO3 (26), glucose (10), and
MgCl2 (4), CaCl2 (0.7) for
storage and MgCl2 (1.3),
CaCl2 (2.3) for recording. The
prelimbic/infralimbic region is that portion of the medial PFC
flanked by the corpus callosum in coronal sections (25).
Slices were perfused by gravity-fed ACSF (maintained at 28-32°C) at
a rate of 1-3 ml per min and viewed by using differential interference
contrast (DIC) optics. The objective was often removed from the bath
during recordings and the fluid level decreased to reduce stray pipette
capacitance. Thick-walled borosilicate pipettes were filled with (in
mM): K-gluconate (130), KCl (10), EGTA (1), MgCl2
(2), NaATP (2), Hepes (10) or KMeSO4 (140), Hepes
(10), NaCl (4), EGTA (1), NaATP (4), TrisGTP (0.3), and phosphocreatine
(14). In some experiments, KCl was omitted and CsCl (135) was
substituted for KMeSO4. QX-314 (2 mM) and/or
DIDS (4,4'-diisothiocyanate stilbene-2,2'-disulfonate) (2 mM) were
added to pipettes in some experiments. Pipettes were connected to the
headstage of an Axoclamp-2B or Axopatch-200A or B amplifier (Axon
Instruments, Foster City, CA) with Ag/AgCl wire. An Ag/AgCl
reference wire or pellet was placed in the bath directly or through an
agar-bridge and by using offset, Vm shifts were
corrected. Voltage-clamp recordings were obtained in continuous single-electrode voltage-clamp (SEVC) mode and filtered at 1 kHz. Access resistance was monitored at the start and end of the recording period, and a ±15% change was deemed acceptable. Signals were digitized by a PCI-MIO-16E1 A/D board (National Instruments, Austin, TX).
Stimulating electrodes were placed within 200 µm of the soma and
constructed from sharpened epoxy insulated tungsten rods (A-M Systems,
Everett, WA). Electrical stimuli consisted of a low-intensity
square-wave pulse (100-150 µs) administered every 15-60 s.
( In all experiments, 10 µM of the full D1/D5 agonist
(±)-6-chloro-PB hydrobromide (SKF-81297) was used except for data
shown in Fig. 1 where the following
D1/D5 agonists were also used at varying concentrations (0.5-50
µM) (±)-SKF-38393, R(+)-SKF-81297, or R(+)-SKF-82957 (Research
Biochemicals, Natick, MA). All D1 agonists were either made up fresh or
stored for up to 2 days at 4°C. During application, the microscope
and overhead lights were extinguished, and the drugs were delivered for
3-5 min to the bath by means of an opaque syringe. In D1 antagonist
experiments, R(+) SCH-23390 was applied continuously to the slices.
Statistics compared average of baseline values obtained 10-15 min
before drug application to the average of all response during the 10- to 40-min period following D1 agonist application, and included all
cells that showed a stable baseline response. For Figs. 1 and
2, the response at each time point was
normalized to the baseline predrug average: normalized value = 100 × (raw value/baseline average value)
Neurobiology
Dopamine D1/D5 receptor modulation of excitatory synaptic
inputs to layer V prefrontal cortex neurons
,
, Division of Basic Medical
Sciences, University of South Dakota School of Medicine, 414 East Clark
Street, Vermillion, SD 57069; and § Department of
Biology, University of California at San Diego, La Jolla, CA 92093
Abstract
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Abstract
Introduction
Methods
Results
Discussion
References
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
)Bicuculline methiodide, I(S),9(R) (2-20 µM) and D() or (±)2
amino-5-phosphonopentanoic acid (APV) (50-100 M), or bicuculline and
6,7-dinitroquinoxaline-2,3-dione (DNQX) or
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 µM) were applied
constantly throughout the entire experiment to isolate non-NMDA or NMDA
excitatory postsynaptic currents (EPSCs), respectively.
100 to give a
percent change for each value relative to the average baseline response
at each time point. For puff experiments, L-glutamatic acid
or NMDA (1-20 mM) was diluted in the bathing solution that contained
combinations of tetrodotoxin (TTX, 250-500 nM), APV (100 µM),
bicuculline (10 µM), or CdCl2 (200 µM)
and applied by means of a patch pipette. For paired pulse experiments,
non-NMDA EPSCs were isolated pharmacologically and paired pulses were
delivered at 50 Hz every 30-60 s. For mini-EPSC (mEPSC) experiments,
slices were bathed in TTX (0.25 to 1 µM) and bicuculline (10-20
µM) while using CsCl pipettes. mEPSCs were analyzed 5 min before
D1 agonist application and for a 5-min period 10 min after the offset
of the D1 agonist. For synaptic depression experiments, 10-15 pulse,
20-Hz trains were delivered every 2 min and cells were held at 58 to
65 mV. Each individual excitatory postsynaptic potential (EPSP) in
the train was measured relative to the voltage just prior to each
stimulus artifact (measure 1 Fig. 4A) or from the
initial voltage before the train onset (measure 2 Fig.
4A). All responses in the train were then normalized
to the average of the first responses in each individual train. The normalized amplitudes of each of the 15 EPSPs/time point were then
averaged across the 5-12 min baseline period and the 10-30 min post
D1 agonist period for each cell to generate 2 vectors of 15 values
each. Repeated measures ANOVAs compared baseline and D1 condition
vectors across neurons.
View larger version (25K):
[in a new window]
Fig. 1.
D1 receptor modulation of NMDA responses in PFC neurons.
(A) Representative synaptic responses. For all traces,
the baseline (control) response is shown at left, the response during
the period of the peak D1 agonist response (>10 min after D1 agonist
offset) is on the right. A D1 agonist (0.5 µM SKF81297) enhanced the
NMDA EPSC. (B) Average percentage change (and SEM) in
NMDA EPSC amplitude over time. (C) Representative traces
showing that the response evoked by puffing NMDA (1 mM, 8 ms) was
enhanced by the D1 agonist (10 µM SKF-81297, black trace) relative to
the baseline response (gray traces) at Vhold = +40 mV.
(D) Average percentage change (and SEM) in postsynaptic
NMDA current amplitude (n = 8).
View larger version (24K):
[in a new window]
Fig. 2.
D1 receptor modulation of non-NMDA responses in PFC neurons.
(A) Representative traces showing that a D1 agonist (1 µM SKF81297) slightly reduced the non-NMDA EPSC. (B)
Average percentage change (and SEM) in non-NMDA EPSC amplitude over
time. (C) Representative traces showing the non-NMDA
response evoked by puffing glutamate (1 mM, 8 ms) in the presence of
APV (100 µM) was unaffected by the D1 agonist (10 µM SKF-81297,
black trace) relative to the baseline response (gray traces) at
Vhold = 80 mV. TTX (500 nM) was also included in the
bathing solution and CsCl containing pipettes were used.
(D) Average percentage change (and SEM) in postsynaptic
non-NMDA current amplitude (n = 8).
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D1 Agonists Selectively Increase the NMDA Component of EPSCs.
Pyramidal cells were recorded from layer V of the prelimbic
cortex (25). Because the agonists we have used lack complete specificity for receptor subtypes, we refer to D1/D5 receptor agonists simply as D1 agonists throughout. D1 agonists added to the
bathing solution produced a slight depression of the amplitude of
nonisolated layer V postsynaptic potentials (PSPs) in PFC neurons (25.3 ± 8.9%, n = 6; data not shown) as
reported (13).
3.5 ± 10%, n = 4; data not shown). Thus,
D1/D5 receptor activation produced a prolonged increase in the NMDA
component of EPSCs.
We next sought to determine the extent to which a postsynaptic
mechanism contributes to these effects. In the sub- and suprathreshold voltage range, Ca2+ currents are activated by
long-lasting glutamate-mediated depolarizations (29-31) and are the
targets of dopamine modulation (25). Therefore, the postsynaptic
response to puff application of NMDA was recorded at +40 mV, where
Ca2+ currents are expected to be inactivated. In
some cells, we also used ACSF containing the voltage-gated
Ca2+ channel blocker Cd2+
(plus TTX and Cs/TEA-filled pipettes). NMDA-mediated responses were
evoked by pressure ejecting NMDA (1-20 mM, 5-20 ms) near the soma.
For cells exhibiting a stable baseline response for >15 min, the
increase in the NMDA current at a Vhold of + 40mV was 30.3 ± 11% [control = 151.9 ± 11 pA, D1
condition = 198 ± 19 pA, F(1,7) = 17, P < 0.01]. Therefore, D1 agonists selectively increase the postsynaptic
sensitivity of NMDA receptors.
D1 Agonists Slightly Reduce Non-NMDA Component of EPSCs Without
Affecting the Postsynaptic Response to Glutamate.
The non-NMDA component of EPSCs was slightly reduced in size
by
about 10%for 10-50 min following application of the D1 agonist [baseline = 84 ± 15 pA, D1 agonist = 74 ± 12 pA, 9 ± 3%, n = 8, F(1,7) = 6.1, P < 0.05; Fig. 1 A and B].
Non-NMDA responses have been reported to exhibit run-down in
dissociated striatal neurons, which was removed by a D1 agonist (32).
In the present study, although D1 agonists never increased the non-NMDA
response, we did not test whether run-down was removed because cells
that did not exhibit a stable baseline response for >10 min were
excluded (n = 14/32). In a group of control cells, we
found that responses stable initially remained unchanged in amplitude
for >50 min (not shown). Therefore, in cells exhibiting a stable
response, D1 agonists had a slight inhibitory influence on non-NMDA
receptor-mediated synaptic currents.
80 mV to avoid contamination
by voltage-gated Ca2+ currents (80 mV was used
rather than +40 mV to ensure there would be no contamination by NMDA
currents). As shown in Fig. 2 C and D, D1
agonists had no effect on the postsynaptic response to glutamate.
Therefore, D1 agonists reduced the non-NMDA component of the EPSC, but
not through a postsynaptic mechanism.
D1 Agonists Produce a Minor Decrease in Release. The reduction in the non-NMDA component of EPSC amplitude with no change in the non-NMDA receptor response to directly applied glutamate indicates that D1 agonists may act presynaptically. Changes in release were assessed by examining the effect of D1 agonists on spontaneous mEPSCs, the progressive block of synaptic responses by MK-801, paired pulse ratios and synaptic depression to 20-Hz inputs.
mEPSCs were recorded in bicuculline and TTX from 15 neurons. For all events across all neurons, the average control mEPSC amplitude was 6.9 ± 0.3 pA and 7.6 ± 0.4 pA following application of the D1 agonist (10 ± 3.8%; Fig. 3 A and B). This observation is consistent with data shown in Fig. 2 C and D, and indicates that D1 agonists did not reduce the postsynaptic non-NMDA current, and, in fact, increased it slightly. In contrast, the mEPSC frequency was reduced from 1.83 ± 0.18 events/s in the control condition to 1.58 ± 0.16 events/s in the D1 agonist condition [14.8 ± 5%, F(1,13) = 6.6, P < 0.05]. This suggests
that D1 agonists slightly reduce the release probability of
glutamatergic synapses.
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6.6 ± 0.8 pA, EPSC with D1
agonist = 4.9 ± 0.7 pA, 20 ± 8%) but did not
affect the ratio of second-pulse response amplitude to the first
[baseline = 1.28 ± 0.11, D1 condition = 1.16 ± 0.08, F(1,9) = 0.4, P > 0.5, n = 10] (Fig. 3E). Thus, the reduction in release detected by
the mEPSC and MK-801 blocking experiments was either too small to
significantly affect paired pulse ratios or was limited to high
probability synapses, which typically exhibit little facilitation.
D1 Modulation of 20-Hz Trains. Unlike paired-pulse facilitation, which mainly reflects changes in low probability synapses, synaptic depression depends largely on the progressive decrease in release probability at higher probability synapses. Synaptic depression may be counteracted by postsynaptic temporal summation of EPSPs (35). Given the voltage-dependence of the NMDA receptor, this summation can be quite nonlinear (36, 37). To assess the effects of D1 agonists on synaptic depression, trains of 15 stimuli were delivered. In vivo, PFC neurons receive trains of inputs from neighboring neurons during the delay period of working memory tasks, in the 20-Hz frequency range (2, 3, 6, 7, 21-24). To explore the consequences of D1 modulation on trains of inputs in the physiological range, synaptic stimulation was therefore delivered at 20 Hz.
We measured the responses to a 20-Hz train of synaptic inputs in two ways. The first measure (measure 1 Fig. 4A) calculated the amplitude of each EPSP from a baseline obtained just before each pulse in the train. This measure controlled for residual depolarization from preceding responses in the train. Responses were normalized to first response in the train. As above, D1 agonists decreased the amplitude of the initial synaptic responses (Fig. 4A). D1 agonists did not, however, significantly affect the paired pulse ratio of the first two synaptic responses [control = 0.79 ± 1.8, D1 condition = 0.87 ± 0.08, F(1,8) = 0.52, P > 0.05] nor the time constant of depression for responses 1-15 [control = 104.9 ± 19 ms, D1 condition = 120.9 ± 17.8 ms, F(1,7) = 1, P > 0.05; Fig. 4B].
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In the present study, D1 agonists produced an increase in the NMDA component of synaptic currents (through a postsynaptic NMDA mechanism) and a small decrease in non-NMDA-mediated responses (through a small decrease in release probability).
Dopamine has diverse and often contradictory effects in different brain regions. In dorsal striatal neurons, dopamine has been reported to depress (27) or have no effect (38) on compound PSPs. Likewise, the non-NMDA response was depressed by D2 receptor activation in some studies (27, 39), not affected in others (38) and increased by D1 receptors and protein kinase A (PKA) in others (26). Although D1 receptor activation has been reported to consistently increase the NMDA response in both striatal and cortical neurons (11, 12, 40-42), studies on dorsal striatal neurons suggest the increase is mediated by PKA (27), whereas, in ventral striatal neurons, it is mediated by protein kinase C (43). In neurons from the hippocampus or nearby cortices, dopamine has been reported to depress both NMDA and non-NMDA responses (44-47) through a PKA-dependent process (44), whereas direct application of PKA has been reported to increase non-NMDA responses (48). In PFC neurons, the effects of dopamine also depends on the dose: low concentrations (<50 µM) increase the NMDA response by means of D1 receptors, whereas, at high concentrations (>50 µM), the NMDA response was depressed by means of activation of D2 receptors (13, 15). Thus, the effects of dopamine are complex and depend on the agonist concentration, the subtype of glutamate, and/or dopamine receptor stimulated, tissue preparation, and brain region studied.
In PFC pyramidal neurons, selective D1 receptor activation
produced a 10-15% decrease in the non-NMDA component of signal EPSCs
and initial EPSPs in a 20-Hz train that were recorded in the presence
or absence of NMDA blockade. These effects were not mediated
postsynaptically (Figs. 2 B and C and
3B) but appeared to be because of reductions in release.
Analyses of mEPSCs and the MK-801 blocking function revealed a small
(
12%) reduction in release probability. This effect appeared to be
too small to influence paired-pulse ratios or the time course of
synaptic depression. A similar dopamine-mediated reduction in release
without consistent effects on paired-pulse ratios has recently been
reported in subicular neurons (47). One possibility is that because D1
agonists reduce high threshold Ca2+ currents
(25), they may limit presynaptic Ca2+ entry and
hence release. The postsynaptic increase in NMDA currents overcame the
small reductions in release, making NMDA EPSCs larger in the D1 agonist
condition. D1 agonists increased later responses to 20-Hz trains by
means of an APV-sensitive mechanism. Because of the slow decay time of
NMDA responses, an increase in NMDA currents would tend to enhance EPSP
summation. This effect would become more relevant during prolonged
depolarizations from high frequency trains (49). Although slight, the
D1/D5-induced reduction of initial responses, and increase in later
responses acted together to equalize EPSPs throughout the train.
Functional Considerations. During delay periods of working memory tasks, deep layer PFC neurons show sustained activity thought to represent the short-term retention of information to plan and organize forthcoming action (23, 50). Recently, computer models have been used to explore the mechanisms responsible for producing sustained firing modes (16-20). Simulations suggest that NMDA currents are crucial for producing sustained activity. Because of their slow decay time constant, these currents produce a nearly constant synaptic drive that could maintain recurrent activity at rates around 20 Hz. Moreover, the voltage-dependence of the NMDA conductance contributes to the selectivity and robustness of delay-period activity because it especially enhances active and depolarized subpopulations of neurons compared with neurons that are hyperpolarized or firing at low rates.
On the other hand, non-NMDA conductances are voltage-independent and evoke only transient depolarizations, thus contributing much less to sustained activity. In fact, strong non-NMDA activated currents actually reduce the robustness of delay activity because they tend to induce synchronous oscillations and increase the impact of brief, interfering inputs and noise (17, 20). Slightly reducing non-NMDA responses and increasing NMDA component of currents biases inputs to act as constant current sources. However, strong non-NMDA mediated currents may be useful in situations that require the integration of new information or fast switching between different representations or response options. Hence, dopamine by means of D1 receptors might switch PFC networks from a mode that favors integration of new information and exploration to a mode that favors robustly maintained recurrent activity in the context of goal-directed behavior over extended periods of time. It is through these mechanisms that dopamine may enhance sustained activity on working memory tasks (2, 3, 6, 7), which is thought to underlie the trial-unique active retention of information within the PFC (50).| |
Acknowledgements |
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We thank Lee Campbell for technical support. We are also grateful to Jane Sullivan, Charles Yang, Stan Floresco, German Barrioneuvo, and Guillermo Gonzales-Burgos for their comments. This work was supported by a grant from the Howard Hughes Medical Institute. J.K.S. was supported by a grant from the National Sciences and Engineering Research Council of Canada and the Howard Hughes Medical Institute. D.D. was supported by a research stipend from the Deutsche Forschungsgemeinschaft.
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Abbreviations |
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PFC, prefrontal cortex; NMDA, N-methyl-D-aspartate; ACSF, artificial cerebrospinal fluid; EPSC, excitatory postsynaptic current; mEPSC, mini-EPSC; EPSP, excitatory postsynaptic potential; APV, 2-amino-5-phosphonovaleric acid.
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Footnotes |
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To whom reprint requests should be addressed. E-mail:
jeremy{at}salk.edu.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.011518798.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.011518798
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, n = 6). (D) The D1 agonist blocking function overlaps with
that of the control if the D1 agonist blocking function was accelerated
by 12% by shifting the x axis. (E)
Histogram representing data from paired pulse experiments.
(Left, black bar) The normalized change in response 1 (P1) in the 10-40 min following application of the D1 agonist.
(Middle, gray bar) The ratio of P2:P1 for the control
condition. (Right, black bar) The ratio of P2:P1 for
responses acquired 10-40 min following application of the D1 agonist.
Pulses were separated by 20 ms, and neurons were recorded under
voltage-clamp in the presence of 10 µM bicuculline and 0.5-2 µM
DNQX by using CsCl/QX-314-filled pipettes.
