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The Journal of Neuroscience, December 15, 1998, 18(24):10553-10565
D1 Receptor in Interneurons of Macaque Prefrontal
Cortex: Distribution and Subcellular Localization
E. Chris
Muly III,
Klara
Szigeti, and
Patricia S.
Goldman-Rakic
Department of Psychiatry and Section of Neurobiology, Yale
University School of Medicine, New Haven, Connecticut 06520-8001
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ABSTRACT |
Working memory performance is influenced by dopamine activation of
D1 family dopamine receptors in the prefrontal cortex; working
memory performance is maximal at moderate stimulation of D1 family
receptors and is reduced by either higher or lower levels of D1
stimulation. The neuronal mechanisms that underlie this complex
relationship are not yet understood. Previous work from this laboratory
has demonstrated that the D1 family receptors, D1 and
D5, are located in different compartments of
pyramidal cells. Here we use an antibody specific to the D1
receptor and double-label immunohistochemistry at the light and
electron microscopic level to demonstrate that D1-like
immunoreactivity (D1-LIR) is also present in interneurons.
D1 receptor is prevalent in parvalbumin-containing interneurons and is less common in calretinin-containing interneurons. At the ultrastructural level, D1-LIR is found associated
with the Golgi apparatus and endoplasmic reticulum in the soma, with the membranes of vesicles in proximal dendrites, and with the plasma
membrane on distal dendrites, where it is often located near asymmetric
synapses. In addition, D1-LIR is also seen in presynaptic
axon terminals, which give rise to symmetric synapses onto dendritic
shafts and soma. These results raise the possibility that the circuit
basis of working memory in the prefrontal cortex involves a
D1-mediated inhibitory component.
Key words:
dopamine; receptor; D1; interneuron; GABA; parvalbumin; calbindin D-28k; calretinin; colocalization; immunofluorescence; electron microscopy; monkey; prefrontal cortex; working memory
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INTRODUCTION |
Prefrontal cortex in the primate is
critical for performance of cognitive tasks, especially those involving
working memory (for review, see Goldman-Rakic, 1986 ), and a disorder of
its function has been implicated in a variety of disease states,
including schizophrenia (Weinberger et al., 1986, 1988; Baxter et al.,
1989). Dopaminergic inputs to this brain region are important for its function; specific lesions of this mesocortical projection have been
shown to impair performance on cognitive tasks as severely as ablation
of the prefrontal cortex itself (Brozoski et al., 1979; Simon et al.,
1980). The D1 family of dopamine receptors (D1 and
D5) are an order of magnitude more abundant in the
prefrontal cortex than D2 family receptors (D2,
D3, and D4) (Farde et al., 1987;
Goldman-Rakic et al., 1990; Lidow et al., 1991), and the actions of
dopamine at D1 family dopamine receptors are essential to working
memory function in both the human and nonhuman primate prefrontal
cortex (Sawaguchi and Goldman-Rakic, 1991, 1994; Williams and
Goldman-Rakic, 1995; Murphy et al., 1996; Müller et al., 1998).
Given the importance of D1 family receptors to the function of
prefrontal cortex, the specific localization of these receptors in the
circuitry of prefrontal cortex might shed light on which aspects of
this circuitry are integral to cognitive function. Receptor binding
studies have shown that ligands specific to D1 family dopamine
receptors bind with higher density in superficial layers (layers
I-IIIa) and deep layers (layers V and VI) than in middle cortical
layers (layers IIIb-IV) (Lidow et al., 1991). Experiments examining
the expression of mRNA coding for the D1 and D5
receptors suggest that D1 is more prevalent than
D5 in the cortex of human and nonhuman primates
(Meador-Woodruff et al., 1996; Lidow et al., 1997), and this may be the
predominant receptor subtype responsible for the cognitive effects of
D1 family agonists and antagonists.
Recently, specific antibodies have been produced to individual dopamine
receptors, allowing their location to be identified with both molecular
specificity and excellent spatial resolution (Levey et al., 1993;
Bergson et al., 1995). In monkey prefrontal cortex, ultrastructural
studies have revealed that D1-like immunoreactivity (D1-LIR) is prevalent in dendritic spines (Smiley et al.,
1994; Bergson et al., 1995), whereas the D5 receptor is
predominately localized on the dendritic shafts of pyramidal cells
(Bergson et al., 1995). These distributions contrast with those
reported for the D2 and D4 receptors, which
have been localized predominately in cortical interneurons (Mrzljak et
al., 1996; Khan et al., 1998). However, immunohistochemical studies
have shown that the D1 receptor is present in GABAergic
neurons in the striatum (e.g., Hersch et al., 1995).
Here we report the results of double-label immunohistochemistry
experiments at the light and electron microscopic level, which reveal
that, in macaque, the D1 receptor is also present in
cortical interneurons. We describe the distribution of the receptor in different interneuron subtypes and its subcellular localization and
speculate on the relevance of these findings to the effects of D1
agonists and antagonists on working memory function.
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MATERIALS AND METHODS |
Tissue from four young adult monkeys (Macaca mulatta)
was used in this study. The monkeys were perfused transcardially with 4% paraformaldehyde, (one monkey) or 4% paraformaldehyde, 0.2% glutaraldehyde, and 15% picric acid (three monkeys) in 0.1 M phosphate buffer (PB, pH 7.4). The brain was post-fixed
in 4% paraformaldehyde for 2 hr and blocked. In some cases the blocks
were placed in an ascending series of sucrose solutions and then frozen
and stored at  70°C. These blocks were later sectioned on a cryostat
at 50 µm. In other cases, blocks were immediately cut on a vibratome at 50 µm. Vibratome sections were collected in PB, rinsed, and placed
in small volumes of 15% sucrose in PB and then frozen in liquid
nitrogen and stored at 70°C for later use.
Immunofluorescence experiments. Cryostat or vibratome
sections from various cortical regions were rinsed in normal PBS
(33 mM phosphate, pH 7.4) and placed in blocking serum (3%
normal goat serum, 1% bovine serum albumin, 0.1% glycine, and 0.1%
lysine in PBS) with 0.3% Triton X-100 for 1 hr. The sections were then placed in a mixture of primary immunoreagents in blocking serum for
36-60 hr at 4°C. The mixture consisted of rat anti-D1
receptor and one of the following: guinea pig anti-GABA, mouse
anti-calbindin D-28k (CB), mouse anti-parvalbumin (PV), or rabbit
anti-calretinin (CR). The sources and dilutions of each immunoreagent
are given in Table 1. The monoclonal
antibody to D1 has been characterized previously by binding
to fusion proteins, transfected cells, and rat brain membranes and
shows no cross-reactivity to other dopamine receptors (Hersch et al.,
1995). After incubation in the primary mixture, the sections were
rinsed in PBS and placed in a mixture of secondary antisera (Table 1).
After 4 hr at room temperature the sections were rinsed and mounted on
gelatin-coated slides and allowed to air dry at 4°C. The sections
were then coverslipped using a glycerol-based media (Vector
Laboratories, Burlingame, CA) and nail polish to seal the coverslip.
Control experiments were performed for each primary immunoreagent
listed in Table 1, in which only one primary immunoreagent was used,
and the secondary antisera used was directed at an appropriate
alternative primary immunoreagent, e.g., mouse anti-PV followed by
CY3-donkey anti-rat. In these controls, only light
autofluorescence and no cross-reactive staining was observed. The
penetration of the antibody to D1 was as good as, or better
than, the penetration of the other immunoreagents. Accordingly, the
quantification of the immunofluorescence experiments was conducted by
identifying interneurons by labeling with GABA, CB, PV, or CR and then
determining the number of these interneurons that contained
D1-LIR. In this way, the difference in the penetration of
the interneuron identifying immunoreagents, e.g., anti-GABA and
anti-PV, affects the number of interneurons identified on each section,
but the percentage that also contain D1-LIR is not
affected.
Sections were examined and photographed using FITC and rhodamine
filter cubes. To quantify the distribution of single- and double-labeled cells, plots were made using the Neurolucida plotting system (MicroBrightField, Colchester, VT). Samples of cortex extending from the pial surface to the white matter 500 µm wide were plotted from cortical areas 46, 9, and 24 (Walker, 1940) and, in the case of
the GABA/D1 immunofluorescent experiments, area 17. These
areas were chosen to represent an area where dopamine and the
D1 receptor have been shown to have functional significance
(area 46) (Williams and Goldman-Rakic, 1995) and areas of dense (areas
9 and 24) and sparse (area 17) dopamine input (Lewis et al., 1987; Van
Eden et al., 1987; Williams and Goldman-Rakic, 1993) where the
significance of D1 receptor action remains to be
established. Individual labeled neurons were viewed, and their location
was plotted at a magnification of 800×. The material was examined
using an FITC filter cube, and once a labeled interneuron was
identified, the filter was changed to the rhodamine filter cube to
determine whether the cell was single- or double-labeled. For the
GABA/D1 experiments, five plots each were made in areas 46, 9, and 24, representing 2265 GABA+ cells, and three plots were made in
area 17, representing 473 GABA+ cells. In the CB/D1 and
CR/D1 experiments, eight plots each were made for areas 46, 9, and 24, representing 1604 CB cells and 3325 CR cells, respectively.
In the PV/D1 experiment, six plots were made for areas 46, 9, and 24, representing 2839 PV cells. The CB antibody weakly stains a
group of pyramidal cells in layer III in addition to strongly labeling
interneurons (Gabbott and Bacon, 1996). In some cases labeled neurons
could be unequivocally identified as having pyramidal or nonpyramidal
morphology, and examples of single- and double-labeled cells with both
morphologies could be found. However, in many cases it was impossible
to ascertain with certainty the type of cell that was labeled.
Accordingly, we did not attempt to restrict our analysis to neurons of
a particular type. Thus, pyramidal neurons may be included in our
analysis of CB-containing neurons, but not of GABA-, PV-, or
CR-containing neurons.
The number of single- and double-labeled neurons was obtained from each
plot. The percentage of interneurons that contained D1-LIR
was obtained for each plot, and means and SDs were calculated. After a
section was plotted, the coverslip was removed, and the sections were
stained for Nissl substance with thionin. The counterstained section
was then used to determine the laminar borders for the plots that had
been generated from that section. ANOVAs were applied to comparisons
between different interneuron populations, different cortical areas,
and different cortical laminae. Post hoc comparisons with
the Tukey honestly significantly different (HSD) test were made
if the ANOVA revealed a significant effect.
Electron microscopy experiments. Vibratome sections from the
prefrontal cortex were thawed in excess cold PBS and then rinsed three
times. The sections were then placed in blocking serum (as above with
0.5% fish gelatin added and without Triton X-100) for 1 hr. They were
then placed in a primary mixture in the same diluent for 36-60 hr. The
mixture consisted of rat anti-D1 and either guinea pig
anti-GABA or mouse anti-PV (used at the same titers as above). After
incubation in primary mixture, the sections were rinsed in PBS and
incubated for 1 hr in a mixture of secondary antisera: biotinylated
goat anti-rat and goat FAB fragment directed against either guinea pig
or mouse IgG and conjugated to a 1.4 nm gold particle (see Table 1).
The sections were then rinsed, and the immunogold signal was
intensified with silver at room temperature in the dark (Nanoprobes,
New York, NY). The length of time for the silver intensification was
determined empirically, and optimal-sized silver particles were
observed after a 2 min incubation in the reaction mixture. The sections
were then rinsed, gold-toned (Arai et al., 1992), rinsed, and incubated
in ABC reagent (Vector) for 1 hr. The presence of peroxidase was
revealed with diaminobenzidine (DAB) using the glucose oxidase method
(Itoh et al., 1979). The sections were then rinsed in 0.1 M
cacodylate buffer, pH 7.4, osmicated in 1% OsO4 for 10 min, rinsed, dehydrated in alcohol and propylene oxide, and then
flat-embedded in Durcupan resin.
Selected regions of area 9 were mounted onto Durcupan blocks. Ultrathin
sections were cut and collected on Formvar-coated slot grids. The grids
were examined on a JEOL 1010 electron microscope, and selected regions
were photographed. Because the two labels differentially penetrate
tissue, only sections from the surface of the block, where both
DAB and gold particles were visible, were examined. To limit the
possibility of false-positive double labeling, we performed the
immunogold staining before the DAB staining, because silver from the
silver intensification step is known to precipitate onto DAB (Smiley
and Goldman-Rakic, 1993). Control experiments, in which the primary
immunoreagents were omitted failed to reveal labeling with either DAB
or immunogold. When only the antibody to D1 was omitted, no
deposition of DAB around silver-intensified immunogold particles was observed.
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RESULTS |
D1/GABA immunofluorescence
Sections of cerebral cortex were stained for both the
D1 receptor and GABA using the immunofluorescence method.
Double-labeled cells could be identified not only on the basis of the
two colors of the fluorochromes but also on the basis of the different
staining pattern of D1 compared with GABA staining. The
D1 antibody produced a reticulated staining pattern in the
soma and proximal dendrites, whereas the GABA antisera produced an even
staining of the soma, which rarely extended into the proximal dendrites
(Fig. 1A,B). Most GABA
neurons contained D1-LIR (Fig.
2A), and there were no obvious distinguishing characteristics that differentiated
GABA+/D1+ from GABA+/D1 cells. In single
plots, the percentage of double labeled cells in areas 9, 46, 24, and
17 varied from 66.5 to 89.4%. Differences between the cortical areas
were not significant (F(3,14) = 0.168;
p > 0.9), and accordingly, the data were pooled,
revealing that 78.2 ± 6.2% of GABAergic interneurons contained
demonstrable D1-LIR.
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Figure 1.
Photomicrographs of immunostained neurons,
illustrating the patterns of label associated with each of the
immunoreagents used in this study. The antibody to the D1
receptor produces a reticulated pattern of label in the cell soma,
which may extend into the proximal dendrites (A).
This reticulated pattern of staining represents the endoplasmic
reticulum and Golgi apparatus of the labeled neuron (see Fig. 5). Many
of the labeled cells have a pyramidal morphology and a prominent apical
dendrite. The antisera to GABA produces a relatively homogeneous
staining of the cell soma and occasionally weakly labels the proximal
dendrites (B). The antisera to calretinin
(C) and the antibodies to calbindin D-28k
(D) and parvalbumin (E)
produce a Golgi-like staining pattern that labels the soma and proximal
and distal neurites, some of which appear to be axons. Scale bar, 30 µm.
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Figure 2.
Photomicrographs of double-label immunofluorescent
staining of cortical interneurons and the D1 receptor
showing colocalization. In all cases, D1-LIR is
demonstrated by CY3 (red), and the different
interneuron types are demonstrated by FITC staining
(green). Most D1+ neurons are
single-labeled and have a pyramidal morphology (e.g., A,
D). Examples of neurons labeled by staining for GABA
(A), CB (B), PV
(C), and CR (D), which also
contain D1-LIR, are shown. Of the four classes of
interneurons, double-labeled PV cells tended to have the largest amount
of D1-LIR, whereas double-labeled CR cells tended to have
the least.
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Colocalization of D1 and calciumbinding
proteins (CaBPs)
Double-label immunofluorescence experiments with antibodies to
D1 and the CaBP (CB, PV, and CR) allowed us to determine
whether D1-LIR was preferentially located on particular
subtypes of GABAergic interneurons. The different CaBPs are found in
largely nonoverlapping populations of GABAergic interneurons in
mammalian neocortex (Hendry et al., 1989; Van Brederode et al., 1990;
Rogers, 1992; Kubota et al., 1994). Once again, identification of
double-labeled cells was facilitated by different staining patterns. In
contrast to the reticulated staining observed with the D1
antibody, the antibodies to the CaBP labeled neurons in a Golgi-like
manner, diffusely staining their soma and usually their dendrites and
axons (Fig. 1C-E). Examples of double-labeled neurons were
observed for all three CaBPs (Fig. 2B-D). Of the
D1+ population, D1 labeling was most dense in
PV cells, least dense in CR cells, and intermediate in CB cells.
The different classes of interneurons varied significantly in their
frequency of colocalization with the D1 receptor in areas 9, 46, and 24. A higher percentage of PV neurons showed colocalization with D1-LIR; CR showed the least colocalization with
D1-LIR and GABA; and CB exhibited intermediate degrees of
colocalization (F(3,69) = 206.117;
p < 0.001). The degree of colocalization with the
D1 receptor did not vary significantly with cortical area (F(2,69) = 0.197; p = 0.822).
Examples of area 46 plots for the four double-label experiments are
shown in Figure 3. The means and SDs,
pooled for all three cortical areas, are as follows: 78.3 ± 6.8%
of GABA+ cells, 79.1 ± 7.0% of CB+ cells, 97.6 ± 1.7% of
PV+ cells, and 41.1 ± 10.5% of CR+ cells were D1+
(Fig. 4). Post hoc Tukey HSD
tests revealed that with the exception of the GABA and CB pair, all
pairwise comparisons were significant (GABA vs PV, p < 0.001; GABA vs CR, p < 0.001; PV vs CR,
p < 0.001; PV vs CB, p < 0.001; CR vs
CB, p < 0.001; GABA vs CB, p = 0.986). These results indicate that GABA+/D1+ neurons include
essentially all PV cells, and that GABA+/D1 neurons
include the bulk of CR neurons.
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Figure 3.
Examples of four plots of single- and
double-labeled interneurons in area 46 showing the different degrees of
colocalization and laminar patterns. Open circles
indicate single-labeled interneurons; filled circles
indicate double-labeled interneurons. Laminar borders are marked on
each plot and indicated by the roman numerals to the
right. Most interneurons stained for GABA
(A) and CB (B) contain
D1-LIR. Almost all PV-stained interneurons contain
D1-LIR (C), whereas most CR-stained
interneurons do not contain detectable D1-LIR
(D). CB+/D1+ neurons are most
prevalent in layer III; the other layers have higher percentages of
single-labeled CB neurons (B). The few PV
interneurons that do not contain D1-LIR tend to be in
layers I and II (C).
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Figure 4.
Graph illustrating the degree to which different
interneuron populations contain D1-LIR. Interneuron
populations were defined by staining for GABA, CB, PV, or CR. The
percentage of neurons in these populations that contained
D1-LIR with SD bars is presented. GABA and CB neurons have
similar degrees of D1 colocalization (75-80%), whereas PV
neurons have markedly higher degrees of D1 colocalization
(98%), and CR neurons have markedly lower degrees (40%).
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We next analyzed the laminar distribution of single- and double-labeled
interneurons in areas 9 and 46 (area 24 was excluded, because this area
lacks a layer IV, making comparisons with six layered neocortex
difficult). The two-way ANOVA for each cell class with factors of
cortical area (areas 46 and 9) and cortical layer (layers I, II, III,
IV, V, and VI) demonstrated that the subpopulations of interneurons
differed in the laminar distribution of single- versus double-labeled
cells. For both GABA neurons and CR neurons, the percentage of
double-labeled, D1-LIR containing neurons did not vary in
the different cortical layers (Table 2). PV and CB neurons, on the other hand, did show significantly different percentages of colocalization with D1 in different cortical
layers (F(5,58) = 3.125; p = 0.014, PV neurons; F(4,68) = 16.300;
p < 0.001, CB neurons; Table 2). Fewer double-labeled
PV neurons were found in layers I and II than in other layers, whereas
the percentage of double-labeled CB neurons peaked in layer III and fell off, both superficially in layer II as well as deeper in layers
IV-VI (Table 2). It is tempting to speculate that this distribution of
double-labeled CB+/D1+ cells is attributable to the
labeling of layer III pyramidal cells by the CB antibody. We have seen
examples of both single- and double-labeled CB+ pyramidal and
nonpyramidal cells. However, without other markers to unambiguously divide CB neurons into pyramidal and nonpyramidal types, quantification of the percentage of colocalization with D1 in these two
populations would not produce reliable results. No effect of cortical
area was found for any of the four cell classes.
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Table 2.
Percentage of interneurons labeled with GABA, CB, PV, or CR
that were also labeled with D1 across the six cortical
layers
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Subcellular localization of D1-LIR in interneurons
Material from double-label experiments was then examined with the
electron microscope to confirm colocalization of D1 in
interneurons and to examine the subcellular localization of
D1 receptor in these neurons. DAB was used to reveal the
presence of D1, and immunogold was used to reveal
the presence of either GABA or PV. This method confirmed the presence
of D1-LIR in both GABA+ and PV+ neurons. Gold particles
were present throughout the cytoplasm and nucleus of labeled neurons.
DAB was observed in the endoplasmic reticulum and Golgi complexes of
both single- and double-labeled cells (Fig.
5A-C). D1-LIR was
not associated with the plasma membrane of the soma or the immediately
adjacent proximal dendrites. This was true for all double-labeled cells
examined as well as for all single-labeled, D1+,
neurons.
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Figure 5.
Electron micrographs illustrating a GABAergic
interneuron that contains the D1 receptor. Gold particles,
representing GABA immunostaining, fill the soma of the neuron.
D1-LIR (DAB, arrows) labels the Golgi
apparatus, shown at higher magnification in B and
C. Scale bars: A, 1 µm; B,
C, 250 nm.
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We focused on D1/PV double-label experiments to
examine the distal dendrites of interneurons for D1-LIR,
both because the PV antibody reliably stained dendrites and axons at
the electron microscopic level, and because the vast majority of PV
neurons contained D1-LIR in our immunofluorescence
experiments. D1-LIR could be identified as patches of DAB
reaction product in PV+, immunogold-stained dendrites. In
large-caliber, presumably proximal PV+ dendrites, D1-LIR
could sometimes be identified (Fig. 6); however, the DAB was always associated with internal membrane structures and never the plasma membrane. Only in smaller-caliber, presumably distal PV+ dendrites were patches of D1-LIR seen
associated with the plasma membrane of the dendrite, as well as with
internal membranes. When followed in serial section, D1
staining associated with the plasma membrane was often located adjacent
to asymmetric synapses onto the PV dendrite (Fig.
7), in a pattern that is reminiscent of
the D1 staining in pyramidal cell spines, which receive
asymmetric synapses.
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Figure 6.
Electron micrograph illustrating D1 in
the proximal dendrite of an interneuron. This large-caliber dendrite of
an interneuron contains parvalbumin (gold particles) and receives an
asymmetric synapse (arrowhead). D1-LIR (DAB,
arrow) is found associated with internal vesicles but
not with the plasma membrane. Scale bar, 400 nm.
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Figure 7.
Electron micrographs illustrating D1
in the distal dendrites of interneurons. Serial sections through two
parvalbumin (gold particles)-containing small-caliber dendrites are
presented. In the first, the dendrite receives an asymmetric synapse
(A, arrowhead). The synapse disappears on
the adjacent sections (B, C), and
D1-LIR associated with the plasma membrane (DAB,
arrow) appears. In the second (D,
E), the dendrite receives an asymmetric synapse
(arrowheads), and D1-LIR is associated with
the plasma membrane, adjacent to the synapse (arrows).
Scale bar, 400 nm.
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In addition to D1 staining in distal dendrites,
D1 was also localized in PV+ axon terminals. Figure
8 illustrates two PV+ axons, identifiable
by the synaptic vesicles that they contain, one of which gives rise to
a symmetric synapse onto an unlabeled dendritic shaft; both profiles
contain D1-LIR. Another example (Fig.
9) contains a patch of
D1-LIR, which, when followed in serial sections, is
adjacent to the presynaptic specialization of a symmetric synapse onto
a cell soma. This also parallels the presence of D1-LIR in
axon terminals that give rise to asymmetric synapses (Bergson et al.,
1995; Hersch et al., 1995).
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Figure 8.
Electron micrographs illustrating D1
in the axons of interneurons. A, Profile of the axon
terminal of an interneuron, containing parvalbumin (gold particles) and
synaptic vesicles (open arrow), which is making a
symmetric synapse onto an unlabeled profile (arrowhead).
D1-LIR is also seen in the terminal associated with the
plasma membrane (arrow). Above the double-labeled axon
terminal is a single-labeled PV+ profile for comparison.
B, Axonal profile that is labeled with parvalbumin and
contains synaptic vesicles (open arrow). D1-LIR is
present in the profile as well as in a nearby dendritic spine
(arrows). Scale bar, 400 nm.
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Figure 9.
Electron micrographs of serial sections through a
double-labeled axosomatic terminal. A parvalbumin-labeled axon terminal
is located adjacent to an unlabeled soma. The terminal makes a
symmetric synapse onto the soma (A-C, arrowheads). As
the synapse leaves the plan of section, D1-LIR appears, associated with
the plasma membrane (E, F, arrows). Scale bar, 400 nm.
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DISCUSSION |
These results demonstrate that the D1 receptor is
present in GABAergic interneurons of macaque cerebral cortex and is
differentially distributed in subtypes of interneurons defined by the
presence of different CaBPs. D1 is seen in ~75% of
neurons labeled for GABA and in a similar percentage of neurons that
contain CB. Almost all PV-containing interneurons (98%) and a minority
of CR-containing interneurons (40%) contain D1-LIR. The
distribution of D1-containing interneurons does not vary
across different cortical areas but does vary across cortical laminae
for some types of interneurons. At the ultrastructural level the
localization of the D1 receptor in interneurons is
analogous to that seen in pyramidal cells, being located in the distal
dendrites of interneurons, adjacent to asymmetric, presumably
glutamatergic synapses, and in presynaptic terminals.
Evidence for D1 in GABAergic neurons
Although previous studies of the D1 receptor in
macaque prefrontal cortex have emphasized its presence in the spines of
pyramidal neurons, there is precedence for D1 family receptors in
GABAergic neurons. Stimulation of D1 family receptors increases the
synthesis and release of GABA in the striatum (Girault et al., 1986;
Steulet et al., 1990; Aceves et al., 1995) and substantia nigra pars
reticulata (Aceves et al., 1992). D1-LIR has been reported
in the medium spiny neurons of the striatum, which are GABAergic
(Hersch et al., 1995; Yung et al., 1995; Surmeier et al., 1996). D1
family receptor stimulation modulates GABA-mediated IPSPs in the
substantia nigra and basal forebrain (Cameron and Williams, 1993;
Momiyama and Sim, 1996) and also augments evoked IPSPs in rodent
prefrontal cortex (Yang et al., 1997). In addition, ligand binding
studies in the rat have suggested that D1 family receptors are
preferentially present in interneurons on the basis of the size of
labeled cells (Vincent et al., 1993). In summary, the literature
supports D1 family- and, in some cases, D1
receptor-mediated effects in GABAergic cells in a variety of
structures. The data reported here extend these findings to macaque cortex.
Implications of the distribution of D1 in different
cortical areas, layers, and interneuron subtypes
Our finding that the percentage of D1-containing
GABAergic neurons does not vary across cortical areas is surprising,
given that the four areas examined receive dopaminergic input of such varying strength (Lewis et al., 1987; Van Eden et al., 1987; Williams and Goldman-Rakic, 1993). However, dopamine produces similar
enhancement of NMDA-gated currents in human brain slices taken from
temporal, frontal, parietal, and occipital cortex, and this effect is
blocked by D1 antagonists (Cepeda et al., 1992, 1993). The cortical
D1 receptor is located extrasynaptically (Smiley et al.,
1994) and may be stimulated by the volume transmission of dopamine
(Chergui et al., 1994; Garris and Wightman, 1994). Furthermore,
dopaminergic afferents in different regions vary in their capacity to
release and take up dopamine such that, in regions with different
densities of dopaminergic inputs, there may be sufficient dopamine
overflow to support volume transmission and stimulate extrasynaptic
D1 receptors (Garris and Wightman, 1994).
We also find that subtypes of interneurons vary in the extent to which
they contain D1. Almost all PV+ cells contain substantial D1-LIR, whereas most CR+ cells have no detectable
D1-LIR, and CB+ cells fall in between these extremes. These
findings parallel those of experiments examining contacts between
dopaminergic axon terminals and interneurons. Axon terminals containing
tyrosine hydroxylase (TH) have been shown to synapse onto subtypes of
GABA-containing neurons in monkey cortex; specifically, TH-containing
terminals synapse onto PV-containing interneurons but not onto
CR-containing interneurons (Sesack et al., 1995; Lewis et al., 1996).
PV+ neurons include basket and chandelier cells that target the
proximal portions of pyramidal cells (DeFelipe et al., 1989; Hendry et
al., 1989; Lund and Lewis, 1993; Condé et al., 1994), CB+ neurons
include neurogliaform cells, which target the distal portions of
pyramidal cells (Kisvarday et al., 1990; Lund and Lewis, 1993;
Condé et al., 1994), and CR+ cells include a subgroup of
double-bouquet cells whose terminals selectively target other
interneurons (Gulyás et al., 1996; Meskenaite, 1997). Thus,
D1-mediated effects on interneurons might be particularly
strong on those cells with the strongest inhibitory effect on cortical
pyramidal cells and weakest on those cells that may target other
inhibitory interneurons and perform a disinhibitory role.
Functional implications
Although the effects of dopamine have long been believed to be
inhibitory, recent evidence suggests that dopamine acting at the
D1 receptor can facilitate neuronal firing (Williams and
Goldman-Rakic, 1995; Yang and Seamans, 1996). Dopamine, acting at the
D1 receptor, enhances glutamate-gated currents,
specifically the NMDA-gated current (Cepeda et al., 1993; Maguire and
Werblin, 1994; Smith et al., 1995; Zheng et al., 1996). A morphological
substrate for the interaction between D1 receptors and
glutamatergic inputs is the location of D1-LIR adjacent to
asymmetric, presumably excitatory and glutamatergic synapses
(Colonnier, 1968; DeFelipe et al., 1988), both on the spines of
pyramidal cells and on the dendritic shafts of nonpyramidal cells (data
presented here and Bergson et al., 1995). Electrophysiological
recordings in the cortex and striatum demonstrate that dopamine can
both enhance neuronal firing directly and increase the inhibitory input
to that neuron (Penit-Soria et al., 1987; Williams and Millar, 1990).
Williams and Millar (1990) have shown in the striatum that the balance
between excitation and inhibition is dependent on the concentration of
dopamine; excitation is seen at low levels of dopamine, whereas at
higher levels of dopamine, inhibition dominates.
This suggests a possible model to explain the inverted U relationship
of D1 activation and working memory performance (Murphy et al., 1996;
Zahrt et al., 1997), as well as the results of D1 occupancy on neuronal
delay period firing (Williams and Goldman-Rakic, 1995). With suboptimal
stimulation of the D1 receptor, excitatory inputs to
pyramidal and nonpyramidal cells support modest delay activity in
pyramidal cells (Fig.
10A). As dopaminergic
stimulation of the D1 receptor increases, enhancement of
excitatory inputs to pyramidal cells becomes maximal, while enhancement
of inputs to interneurons is still modest, and the delay activity in
pyramidal cells reaches a maximum (Fig. 10B). As
dopaminergic stimulation of the D1 receptor increases
further, the enhancement of excitatory inputs to interneurons
reaches a maximum, and the enhancement of inputs to pyramidal
cells plateaus. In this state, the delay activity in pyramidal cells is
limited because of D1-mediated feed-forward inhibition
(Fig. 10C).
View larger version (17K):
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|
Figure 10.
Model for the relationship between D1 receptor
stimulation and the strength of cortical activity during the delay of a
working memory task. Dopamine, acting at D1 receptors, enhances
glutamatergic inputs acting on the NMDA receptor. At low levels of
dopamine release (A), these inputs are not
enhanced to either pyramidal neurons or interneurons. At moderate
levels of dopamine release, the glutamatergic inputs to pyramidal cells
are primarily enhanced, leading to an increase in pyramidal cell delay
activity (B). At high levels of dopamine release,
the glutamatergic inputs are enhanced to both pyramidal cells and
interneurons, leading to a reduction in pyramidal cell activity by
feed-forward inhibition (C).
|
|
Two lines of evidence support the possibility of differential
effectiveness of dopamine at D1 receptors in pyramidal
versus nonpyramidal cells. First, in macaque prefrontal cortex,
pyramidal cell dendrites have a higher density of close contacts with
TH-containing axon terminals than interneuron dendrites (Krimer et al.,
1997). Thus pyramidal cells may be in closer proximity to dopamine
release sites than interneurons, and their D1 receptors
might be maximally stimulated more readily than the D1
receptors of interneurons. Second, the D1 receptor acts via
a second messenger cascade that includes cAMP (Gingrich and Caron,
1993), which can diffuse from the site of its production (Hempel et
al., 1996). Although the specific mechanism that underlies the
interaction between D1 family receptor stimulation and altered
glutamate-gated channel currents is not known, it likely involves this
second messenger cascade. On pyramidal neurons, the spine can act as a
biochemical compartment to restrict the diffusion of second messenger
away from the associated asymmetric synapse and to maintain a high
concentration for maximal effect (Müller and Connor, 1991; Koch
and Zador, 1993). On nonpyramidal neurons, the location of the
D1 receptor and asymmetric synapse on the dendritic shaft
might allow for more diffusion and thus a lower concentration of second
messengers and reduced effect at the asymmetric synapse. This model
remains to be tested; nevertheless, the results presented here suggest
that the impact of dopamine on working memory may involve actions on
both nonpyramidal as well as pyramidal neurons.
| |
FOOTNOTES |
Received July 17, 1998; revised Sept. 17, 1998; accepted Sept. 22, 1998.
This work was supported by National Institutes of Health Grant
MH44866 and a Pfizer postdoctoral fellowship to E.C.M. We thank G. Williams, N. Vnek, and L. Mrzljak for helpful discussions.
Correspondence should be addressed to E. Chris Muly III, Department of
Psychiatry, Yale University School of Medicine, P.O. Box 208001, C303
Sterling Hall of Medicine, 333 Cedar Street, New Haven, CT 06520-8001.
| |
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Copyright © 1998 Society for Neuroscience 0270-6474/98/182410553-13$05.00/0
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Top
Abstract
Introduction
