1 Departments of Psychiatry and , 2 Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15213, USA
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Abstract |
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Introduction |
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Subclasses of cortical GABA neurons have been identified by electrophysiological and morphological criteria (Lund and Lewis, 1993; Kawaguchi and Kubota, 1997
). In addition, different subclasses of GABA neurons may be distinguished by the presence of specific calcium-binding proteins (DeFelipe, 1997
). For example, parvalbumin (PV)-containing neurons include chandelier cells and basket-like, wide-arbor neurons, whereas calretinin (CR) is present in double bouquet cells (Lund and Lewis, 1993
; Condé et al., 1994
; Gabbott and Bacon, 1996a
). In addition, in monkey PFC, PV-containing cells comprise ~25% of GABA neurons, whereas CR-containing cells constitute ~50% of GABA neurons (Condé et al., 1994
; Gabbott and Bacon, 1996b
). Although both PV- and CR-containing cells are present across cortical layers, they are differentially weighted to particular layers. For example, in monkey PFC, CR-containing cells are predominantly located in layer 1 to superficial layer 3, whereas PV-containing neurons are most dense in layers deep 34 (Condé et al., 1994
; Gabbott and Bacon, 1996a
).
The calcium-binding protein subclasses of GABA cells can be further distinguished by their synaptic targets. For example, PV-containing chandelier and wide-arbor neurons (Lund and Lewis, 1993; Condé et al., 1994
; Gabbott and Bacon, 1996a
) provide the most proximal inhibitory input to pyramidal neurons. Specifically, the axon terminals of chandelier cells are arrayed in distinctive vertical clusters that form Grays Type II synapses onto the axon initial segments of pyramidal cells (Somogyi, 1977
; Freund et al., 1983
; DeFelipe et al., 1985
), and wide-arbor neurons (Lund and Lewis, 1993
), similar to large basket cells located in sensory cortices, form inhibitory synapses onto the somata and proximal dendritic shafts and spines of pyramidal cells (Freund et al., 1983
; Williams et al., 1992
). In contrast, CR-containing neurons appear to contact primarily other GABA neurons. For example, in the superficial layers of visual cortex in both rats (Gonchar and Burkhalter, 1999
) and monkeys (Meskenaite, 1997
), as well as in rat hippocampus (Gulyás et al., 1996
), the majority of CR- labeled axon terminals form Grays Type II synapses onto GABA-containing dendritic shafts and somata. Some of these postsynaptic targets are also CR-immunoreactive (Gulyás et al., 1996
; Gonchar and Burkhalter, 1999
).
The activity of these different subclasses of GABA cells depends, in part, upon the source and amount of synaptic inputs that they receive. Interestingly, recent studies suggest that different classes of GABA neurons receive discrete inputs. For example, in rat barrel cortex, PV-containing interneurons are the major GABA cell class to receive excitatory input from the ventroposteromedial thalamic nucleus (Staiger et al., 1996). Similarly, in monkey PFC, dopamine inputs preferentially target PV-labeled dendrites (Sesack et al., 1998
) and not CR-labeled dendrites (Sesack et al., 1995a
). In addition, in rat hippocampus, an ultrastructural study revealed that PV-containing neurons receive a greater total amount of excitatory synaptic input than do CR-containing neurons (Gulyás et al., 1999
). Although this study did not identify the source of the excitatory synapses, it does suggest that GABA neurons differ in the amount of input they receive.
Given these differences across cell classes, the role of GABA neurons in working memory processes may be further informed by determining the sources of excitatory inputs to different types of GABA neurons. We previously demonstrated that both the associational and long-range intrinsic axons of supragranular pyramidal neurons in monkey PFC target almost exclusively the dendritic spines of other pyramidal cells (Melchitzky et al., 1998), whereas ~50% of the local axon collaterals (within 300 µm of the cell body) of these neurons form synapses onto the dendrites of GABA neurons (Melchitzky et al., 2001
). Although these GABA neurons include the PV-containing subclass (Melchitzky et al., 2001
), it is unknown whether other local circuit neurons receive such input, whether this input differs as a function of laminar location, and whether these inputs reflect the relative amount of excitatory inputs to different GABA cells. Thus, in this study, we used dual-labeling electron microscopy to examine excitatory synapses onto PV- and CR-labeled dendrites in different layers of monkey PFC.
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Methods |
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Tissue sections from the same three male, adult cynomolgus monkeys (Macaca fascicularis) used in our previous study (Melchitzky et al., 2001) were examined in this study. All animals were treated according to the guidelines outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals, as approved by the University of Pittsburghs Animal Care and Use Committee. As previously described, animals were anesthesized, placed in a stereotaxic apparatus, and a craniectomy was performed over the dorsal PFC. Iontophoretic injections of 10% biotinylated dextran amine (BDA; 10 000 MW; Molecular Probes, Eugene, OR) were made by passing positive current (5 µA, 7 s cycles) through glass pipettes (tip diameter 2030 µm) for 10 min. Injections were centered at a depth of 1.2 mm below the pial surface in PFC area 9 (Walker, 1940
). As shown in Figure 1A
, one injection was made in each animal in either the right (two monkeys) or left (one monkey) hemisphere. After a survival time of 812 days, monkeys were deeply anesthetized and then perfused transcardially with room temperature (29°C) 1% paraformaldehyde and 0.05% glutaraldehyde in 0.1 M phosphate buffer (PB), pH 7.4, for 5 s followed by 4% paraformaldehyde and 0.2% glutaraldehyde in 0.1 M PB, pH 7.4, for 9 min at a flow rate of 350400 ml/min. The brains were then removed, and coronal blocks (56 mm thick) containing the BDA injection sites were immersed in cold 4% paraformaldehyde for 2 h. For all animals, following post-fixation, tissue blocks were washed in 0.1 M PB, pH 7.4, and sectioned coronally on a Vibratome at 50 µm.
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Definition of Neuronal and Synaptic Elements
Neuronal elements of relevance to this study were identified using the criteria of Peters et al. (Peters et al., 1991). Axon terminals were gener- ally >0.2 µm in diameter and contained synaptic vesicles and often mitochondria. Dendritic shafts were characterized by the presence of mitochondria, numerous microtubules and neurofilaments, as well as synaptic specializations. Dendritic spines were identified by the absence of both organelles and microtubules and by the presence of a spine apparatus (in optimal planes of section). Grays Type I synapses (Gray, 1959
) were characterized by widened and parallel spacing of apposed plasmalemmal surfaces, and a thick postsynaptic density. Furthermore, the axon terminals forming these synapses contained round synaptic vesicles. In contrast, Grays Type II (Gray, 1959
) synapses had thin postsynaptic densities, intercleft filaments, and synaptic vesicles that were usually pleomorphic in shape.
Sampling Regions and Procedures for BDA-labeled Terminals
In order to identify the targets of local axon collaterals of supragranular pyramidal neurons, BDA-labeled axon terminals located in zones ~300 µm from the core of the BDA injection site were sampled (Fig. 1). From each animal, one or two trapezoid blocks were taken from both layers 2 and 3a and layer 3b (Fig. 1D
). Coronal blocks were sectioned on a Leica ultramicrotome at 80 nm and three to six ultrathin sections were collected on individual 200 mesh copper grids. The grids were subsequently counterstained with uranyl acetate and lead citrate, and examined on a JEOL 100 CX electron microscope. For each block, two or three grids (separated by at least 10 and at most 20 grids) were analyzed. One section per grid was randomly chosen as the starting point for analysis. Within this section, all BDA-labeled axon terminals within fields of specific CR- or PV-labeling were identified and photographed at x19 000. BDA-labeled axon terminals were considered to be within a field containing specific CR or PV labeling if both labeled elements were encompassed by an electron micrograph at x10 000 magnification (66.5 µm2). All profiles of BDA-labeled axon terminals were followed in limited (
4) serial sections.
For those terminals that had an identifiable synaptic specialization in any of the serial sections, the post-synaptic target was determined. The terminal was then placed into one of the following categories: (i) synapse onto immunolabeled dendrite, (ii) synapse onto unlabeled dendrite, or (iii) synapse onto unlabeled spine. Those terminals without a definite synaptic specialization were excluded from further analyses. In order to avoid false-negative results in the dual-labeled tissue, we sampled only from areas of the trapezoid blocks that contained the tissueepon interface and we only analyzed fields that contained both specific peroxidase and goldsilver immunolabeling (Sesack et al., 1998).
The proportions of BDA-labeled terminals targeting CR- and PV- labeled dendrites were compared using two-sided, 2 x 2 chi-square analyses. The data presented in Results for inputs to PV-labeled dendrites in layer 3b have been previously reported (Melchitzky et al., 2001).
Determination of the Relative Amount of Excitatory Input to Immunolabeled Dendrites
In order to determine the relative amount of synaptic input to CR- or PV-immunoreactive (IR) dendritic shafts, random fields containing CR- or PV-IR dendritic shafts from the sections used for sampling the synaptic targets of local axon terminals were photographed at x19 000. Using a computer digitizing system (MCID M5; Research Imaging Inc., St Catherines, Ontario, Canada), the perimeter of each labeled dendritic shaft was outlined to determine the length of the dendritic membrane. In addition, for each apposed, unlabeled axon terminal, the length of the apposition was measured. Measurements were made by two investi- gators, both of whom were blind to dendritic category and layer. The within-rater reliability of length measurements was confirmed by an intraclass correlation coefficient (ICC) of 0.999 [95% confidence interval (CI) = 0.9980.999]. A between-rater ICC of 0.999 (95% CI = 0.9980.999) demonstrated the consistency of measurements.
The apposed, unlabeled axon terminals were divided into three categories based upon their synaptic specialization in reference to the labeled dendritic shaft in this single section analysis: (i) apposition without an identifiable synaptic specialization, (ii) Grays Type I synapse or (iii) Grays Type II synapse. Terminals in category 1 that clearly synapsed onto another structure in the neuropil were considered unlikely to also form a synapse onto the immunolabeled dendrite (Kisvárday et al., 1986; McGuire et al., 1991
) and were excluded from further analysis. To determine the proportion of labeled dendrite membrane length that was contacted by unlabeled axon terminals, the ratio of the sum of the lengths of apposed terminals for each dendrite to the total length of the dendritic membrane was computed. In addition, the proportion of dendritic membrane apposed by terminals forming Type I synapses was also calculated. Differences in these proportions were compared using a two-way analysis of variance (ANOVA) with type of labeled dendrite (i.e. PV- or CR-labeled) and layer as the main effects. Because the focus of this portion of the study was on the relative amount of excitatory input to PV- and CR-IR dendrites, the terminals forming Type II synapses were not analyzed. In addition, the use of a single section analysis results in an underestimation of the number of inputs from Type II synapses because their thin postsynaptic density and small synaptic size make Type II synapses more difficult to identify in, and less likely to be sampled by, single sections.
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Results |
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In the tissue examined, BDA-containing terminals were well-labeled and abundant. However, the goal of this part of the study was to determine if BDA-labeled terminals differentially contacted PV- and CR-IR dendritic shafts. Therefore, in order to avoid confounds introduced by potential differences in the penetration of the antibodies (Sesack et al., 1995b), we quantified only those BDA-labeled axon terminals that were located in the same field (66.5 µm2) as either a PV- or CR-labeled structure. The amount of dual-labeled tissue sampled for CR-containing fields was 314 095 µm2 and 409 976 µm2 for layers 23a and layer 3b, respectively. For PV-containing fields, the amount of tissue sampled was 360 381 µm2 for layers 23a and 254 581 µm2 for layer 3b. Within these fields, 264 BDA-labeled terminals met the specified criteria and were further analyzed. Of these terminals, 110 were from monkey CM214, 88 from monkey CM222 and 66 from monkey CM223.
Differential Targeting of CR- and PV-labeled Dendritic Shafts
In layers 23 of monkey PFC, local axon terminals were found to contact both PV- (Fig. 2A) and CR-labeled (Fig. 2B
) dendritic shafts. In fields containing both BDA and PV labeling, 48% (55/115) of the BDA-labeled, local axon terminals were apposed to PV-IR dendrites, a proportion that was significantly greater (
2 = 12.70; P < 0.001) than the 23% (20/86) of local terminals apposed to CR-IR dendrites in fields containing both BDA and CR labeling. A more marked difference in target specificity was observed when only BDA-labeled local axon terminals with identifiable Type I synapses were examined. Specifically, 34% (10/29) of these terminals formed synapses onto PV-IR dendritic shafts, whereas only 3% (1/34) synapsed onto CR-IR dendritic shafts (
2 = 10.8; P = 0.002). Of the 63 terminals with identi- fiable Type I synapses, 22 were from monkey CM214, 28 from monkey CM222, and 13 from monkey CM223.
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In addition to contacting labeled dendrites, BDA-labeled axon terminals also formed synapses onto unlabeled dendrites and spines (see Fig. 3), but not cell bodies (labeled or unlabeled). In both the PV- and CR-labeled tissue, approximately one half of the local axon terminals with identifiable Type I synapses targeted dendritic shafts; in the PV condition these shafts were pre- dominantly PV-IR, whereas in the CR condition almost all the targeted dendritic shafts were unlabeled (Fig. 3
). As expected from our previous findings (Melchitzky et al., 2001
), ~50% of the local axon terminals targeted dendritic spines in both the PV and CR conditions (Fig. 3
).
Overall Relative Synaptic Input to PV- and CR-labeled Dendritic Shafts
To determine whether the proportions of BDA-labeled axon terminals that contacted PV- and CR-labeled dendritic shafts, reflected the relative densities of all terminals contacting these two populations, we obtained estimates of the overall synaptic input to each class of dendrite. As shown in Table 1, neither the mean length of membrane per labeled dendrite, nor the mean length of apposed axon terminals differed as a function of calcium binding protein or layer. However, two-way ANOVAs revealed that both the number of apposed axon terminals [F(1,115) = 10.69, P = 0.001] and the proportion of dendritic length apposed by all axon terminals [F(1,115) = 12.32; P = 0.001] were significantly greater for PV- than for CR-labeled dendritic shafts. The same analyses revealed no effect of layer or an interaction between layer and type of labeled dendrite.
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Discussion |
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The targeting of PV-containing dendrites by these excitatory axon terminals does not appear to be an artifact of technical or sampling issues. For example, even though the immunogold method is less sensitive than immunoperoxidase staining (Chan et al., 1990), the preembedding immunogold technique used in this study provides greater sensitivity than postembedding methods (Chan et al., 1990
; Pickel et al., 1993
). Thus, although the relative incidence of BDA-labeled, local axon terminals forming synapses onto PV- and CR-IR dendrites may have been underestimated, the degree of this effect would not be expected to differ between the two immunolabels. Furthermore, any differences in the sensitivity of the two antibodies or in the relative densities of PV- and CR-labeled dendritic profiles would not confound our results because our sampling method required the presence of both BDA and PV or CR labeling in the same field (Sesack et al., 1995b
). The absence of bias in this sampling approach is supported by the finding that the proportions of BDA-labeled terminals forming synapses onto dendritic spines were similar in the PV- (45%) and CR-labeled (47%) tissue.
Our observation that PV-IR dendrites appear to receive a greater overall density of excitatory inputs than do CR-IR dendrites replicates previous observations in rat hippocampus (Gulyás et al., 1999). Neither this finding, nor the observation that local axon terminals of pyramidal neurons preferentially target PV-IR rather than CR-IR neurons, appear to be a consequence of a greater prevalence of PV- than CR-labeled neurons and dendrites in layers 23 of monkey PFC. First, previous studies have documented that PV-containing cells represent ~25% of GABA neurons, whereas CR-containing cells constitute ~50% of GABA neurons in monkey PFC (Condé et al., 1994
; Gabbott and Bacon, 1996b
). Second, neither the number nor mean membrane length of the labeled dendrites examined differed between PV- and CR-labeled dendrites (Table 1
), and the amount of tissue examined for PV- and CR-IR dendrites was of similar magnitude (723 988 µm2 and 668 025 µm2, respect- ively), suggesting that the densities of PV-IR and CR-IR dendrites are similar in layers 23 of monkey PFC.
The single section analysis utilized in the present study clearly underestimates the total number of Type I synapses onto labeled dendrites. Indeed, the number of terminals apposed to labeled dendrites is threefold greater than the number of Type I synapses (see Table 1), and it is likely that many of these apposed terminals form synaptic specializations onto immunolabeled dendrites in other sections. However, despite these limitations, single section analyses do provide reliable, relative comparisons of synaptic inputs to PV- and CR-labeled dendrites. The synaptic contacts between BDA-labeled terminals and unlabeled dendritic shafts in layers 23a of both the PV- and CR-labeled tissue raises the question of the cell class that receives this input. Unfortunately, the majority of these dendritic shafts were cut in cross-section, and thus many of the hallmark morphological characteristics of interneuron dendrites, such as a varicose shape and a high degree of synaptic input (Smiley and Goldman-Rakic, 1993
; Sesack et al., 1995b
), could not be assessed. Therefore, the dendritic shafts in layers 23a contacted by the local axon terminals could belong to another subclass of GABA neurons and/or to pyramidal cells. Several studies have demonstrated that in combination, the three calcium binding proteins, PV, CR and calbindin (CB), label ~90% of GABA neurons in a cortical region, with CB-containing interneurons comprising ~25% of the GABA cells in monkey PFC (Condé et al., 1994
; Gabbott and Bacon, 1996b
). However, in many cortical areas, including the PFC, CB is also present in a subpopulation of pyramidal neurons in layers 23 (DeFelipe and Jones, 1992
; Condé et al., 1994
; Gabbott and Bacon, 1996a
). Therefore, the identification of synapses from local axon terminals of supragranular pyramidal neurons on CB-IR dendrites in layers 23a would not unambiguously define the cell class targeted.
Implications for the Functional Architecture of the Primate PFC
The axons of supragranular pyramidal neurons in monkey PFC furnish three major types of projections: (i) principal axons that pass through the white matter and terminate in other cortical regions, (ii) long-range axon collaterals that travel parallel to the pial surface through the gray matter, giving rise to a series of stripe-like clusters of axon terminals, and (iii) axon collater- als that arborize locally, within 300 µm of the cell body (Goldman-Rakic and Schwartz, 1982; Freund et al., 1990
; Kritzer and Goldman-Rakic, 1995
; Pucak et al., 1996
; Melchitzky et al., 1998
). For both the corticocortical connections and long-range projections, ~95% of the axon terminals synapse onto the dendritic spines of other pyramidal cells (Melchitzky et al., 1998
). In contrast, only 50% of the local axon terminals synapse onto dendritic spines and the remaining 50% contact the dendritic shafts of GABA cells (Melchitzky et al., 2001
). The findings of the present study, that these local axon collaterals of supragranular pyramidal neurons appear to be preferentially directed to the PV- and not the CR-containing class of GABA neurons, provide insight into the possible functional role of these connections. In concert with previous studies (see Introduction), PV-containing neurons appear to be specialized to receive and furnish direct synaptic connections with pyramidal cells. Not only do the local axon terminals of supragranular pyramidal neurons predominantly form synapses onto PV-IR dendrites in layer 3b of the PFC, but the density of Type 1 excitatory synapses is 4090% greater on PV- than CR-IR dendrites (see Table 1
). This greater relative density of excitatory synapses on PV- than CR-IR dendrites may reflect distinct functional properties of PV-IR neurons. For example, electro- physiological recordings in an in vitro slice preparation of monkey PFC have revealed that fast-spiking neurons, which include cells having the morphological features of PV-IR neurons, exhibit significantly shorter duration of EPSPs than do other classes of GABA neurons (González-Burgos et al., 2002
). These findings suggest that, compared to other classes of interneurons, PV-IR neurons may require a larger number of inputs to integrate and fire.
These findings may reveal an anatomical basis for the role of GABA-mediated inhibition in the working memory processes subserved by the primate PFC. On the basis of both circuitry analyses (Goldman-Rakic, 1995; Pucak et al., 1996
; Lewis and Gonzalez-Burgos, 1999
) and modeling (Wang, 2001
) studies, it has been suggested that reverberating circuits among recip- rocally connected populations of pyramidal neurons may contribute to the sustained firing of PFC neurons during the delay period of working memory tasks. In addition, in vivo recordings in monkey PFC have revealed that, similar to pyramidal cells, fast-spiking GABA neurons exhibit delay-period activity, and that adjacent pyramidal and GABA cells share similar tuning properties (Wilson et al., 1994
; Rao et al., 1999
, 2000
). In vitro studies in rodent and monkey PFC suggest that these fast-spiking GABA cells include the PV-containing subclass (Kawaguchi, 1993
, 1995
; Krimer and Goldman-Rakic, 2001
; Krimer et al., 2002
). Thus, the local, bi-directional connections between supragranular pyramidal neurons and PV-IR GABA cells may be a critical substrate for the regulation of working memory-related neuronal firing in the PFC. In this regard, given the critical role of PFC dopamine in the regulation of working memory processes (Sawaguchi and Goldman-Rakic, 1991
; Williams and Goldman-Rakic, 1995
; Murphy et al., 1996
; Arnsten and Goldman-Rakic, 1998
), it is interesting that among GABA neurons, PV-IR neurons preferentially receive synaptic inputs from dopamine axons (Sesack et al., 1995a
, 1998
) and express the dopamine D1 receptor (Muly et al., 1998
).
In conclusion, the results of the present study provide further evidence of the specificity of intrinsic synaptic connectivity in the monkey PFC, and may reveal anatomical substrates for the inhibitory processes that appear to be central for regulating pyramidal cell firing during different phases of working memory tasks (Constantinidis et al., 2002).
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Notes |
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Address correspondence to David A. Lewis, Western Psychiatric Institute and Clinic, Biomedical Science Tower, W1651, 3811 OHara Street, Pittsburgh, PA 15213, USA. Email: lewisda{at}msx.upmc.edu.
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