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Previous Article | Next Article
Volume 16, Number 10, Issue of May 15, 1996 pp. 3397-3411
Copyright ©1996 Society for NeuroscienceInterneurons Containing Calretinin Are Specialized to Control Other Interneurons in the Rat Hippocampus
Attila I. Gulyás, Norbert Hájos, and Tamás F. Freund Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1450, Hungary
ABSTRACT
Spine-free calretinin-immunoreactive (CR-IR) interneurons form a subpopulation of GABAergic cells in the rat hippocampus. A characteristic feature of these cells
located in all areas and layers
Radially running dendrites of CR-IR cells, located in different layers, intermingled into long braids. An average cell was in contact with dendrites of three to seven other CR-IR cells. Reconstruction of the dendritic trees from six consecutive sections demonstrated that at least 15 cells may participate in a dendro-dendritically connected cluster. Electron microscopical examination revealed that regularly spaced zonula adherentia connect the touching dendrites.
The postsynaptic targets of CR-IR neurons have been examined using postembedding immunogold staining for GABA. CR-containing GABA-immunoreactive axons of local origin formed multiple symmetrical synaptic contacts (two to five) exclusively on GABAergic dendrites (CR-negative as well as CR-positive). Two to 10 CR-IR axons may converge onto a single CR-IR neuron, often from cells belonging to the same dendro-dendritically connected cluster. Using double immunocytochemistry, CR-IR cells were shown to heavily innervate calbindin D28k-containing interneurons and VIP-containing basket cells but avoided the parvalbumin-containing basket and axo-axonic cells.
The unique connectivity of CR-IR cells may enable them to play a crucial role in the generation of synchronous, rhythmic hippocampal activity by controlling other interneurons terminating on different dendritic and somatic compartments of principal cells.
Key words: GABA; nonpyramidal cells; disinhibition; inhibition; dendro-dendritic contacts; oscillation; gap junction; VIP; cholecystokinin
INTRODUCTION
All cerebral cortical areas are composed of two basic types of neurons. The numerous excitatory principal cells give rise to extensive local as well as distant connections terminating primarily on other excitatory neurons. The less numerous group of GABAergic inhibitory cells arborize in most cases only locally (interneurons), and control the activity of excitatory neurons. In the hippocampus, anatomical and physiological studies revealed a wide spectrum of different inhibitory interneurons with considerable differences both in physiological parameters and in the dendritic, as well as axonal arborization pattern (Kawaguchi and Hama, 1987; Lacaille and Schwartzkroin, 1988a
Using immunocytochemistry, the interneurons can be classified also on the basis of their neurochemical marker content (calcium binding proteins or neuropeptides). Neurons containing calretinin (CR), parvalbumin (PV), calbindin-D28k (CB), cholecystokinin (CCK), VIP, NPY, and somatostatin (SOM) were shown to form distinct populations (Kosaka et al., 1985
As a result of multiple studies using different approaches, it appears that there is a high precision in the termination pattern of inhibitory neurons (Somogyi et al., 1983
The types, distribution and anatomical properties of CR-IR neurons in the hippocampus have been described previously (Gulyás et al., 1992
MATERIALS AND METHODS
Male Wistar rats (Charles River, Budapest, 250 gm) were perfused under deep Equithesine anesthesia (chlornembutal 0.3 ml/100 gm), first with physiological saline (1 min) and then, in the case of series A (n = 8 animals), with 300 ml of fixative containing 1% glutaraldehyde (TAAB), 3% paraformaldehyde (TAAB), and 0.2% picric acid in phosphate buffer (PB). For series B the animals (n = 6) were perfused using the following fixative: 0.05% glutaraldehyde, 4% paraformaldehyde, and 0.2% picric acid dissolved in 0.1 M PB, pH 7.4. After fixation, the dorsal hippocampi were dissected together with the overlying neocortex and sectioned on a Vibratome at 80 µm. In the case of series A, the sequence of the sections was preserved to allow serial reconstruction of axonal and dendritic arbors after immunostaining. After extensive washes in PB, the sections were immersed in a mixture of 25% sucrose and 10% glycerol in 0.01 M PB and freeze-thawed in liquid nitrogen to increase the penetration of antisera during immunostaining. After repeated washes, the sections from animals of series A were treated with 1% NaBH4 for 30 min to reduce free aldehyde groups and enhance immunostaining. Pre-embedding immunostaining for CR The sections from animals fixed with fixative A were incubated first in 20% NGS (for 45 min) and then in rabbit anti-CR antiserum (Rogers, 1989-DAB-4HCl (DAB, Sigma, St. Louis, MO) as a chromogen.
After the final washes in PB the sections were treated with 1% OsO4 for 1 hr, dehydrated in ethanol, and embedded in Durcupan (ACM, Fluka, Neu-Ulm, Germany). Selected areas of the embedded sections were re-embedded for further ultrathin sectioning and immunogold staining for GABA.
Double pre-embedding immunostaining First the CR-IR cells were visualized in sections deriving from animals of series B, using the same method as above, with some alterations. The buffer contained 0.5% Triton X-100 during the 20% NGS step and DAB/nickel reaction was used to visualize CR-IR elements in black (Wouterlood et al., 1987Controls. The specificity of the primary antisera have been tested extensively by the laboratories of origin (see references above). Controls of the methods in the present experiments included replacement of the primary antisera with normal rabbit serum (1:200). In these sections, no staining was visible apart from a faint background limited to the surface of the sections. In double-stained sections, the pattern of immunoreactivity for both antigens was identical to that seen in single-stained material.
Replacement of the GABA antiserum with normal rabbit serum in the postembedding immunogold reaction resulted in a loss of specific staining, that is, no signs of colloidal gold accumulation could be detected over any profiles.
RESULTS
Distribution of CR-IR elements in the hippocampus
The distribution and dendritic morphology of CR-IR neurons were similar to that described in detail earlier (Gulyás et al., 1992In the paper in which the characteristics of these cells were first reported (Gulyás et al., 1992
The other, rather large group (13% of the hippocampal GABAergic cells; Miettinen et al., 1992
Fig. 1. Demonstration of the frequency of dendro-dendritic and axo-dendritic contacts among CR-IR neurons at the light microscopic level. A, Low-power micrograph of a 250-µm-wide column of the CA1 region. CR-IR axons (arrowheads), dendrites, and somata can be found in all layers. The radially oriented processes often cross several laminar boundaries. Arrows with letters (B-G) identify those parts that are shown at higher magnification. B-G, High-power light micrographs of selected examples of dendro-dendritic (arrowheads) and axo-dendritic (arrows) contacts from the area shown in A. Note the dendro-dendritic contact in C where two dendrites run attached for more than 200 µm (contact continued in top of D). Scale bars: A, 50 µm; B-G, 10 µm.
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Fig. 4. Multiple contacts between CR-IR axons and dendrites. A, B, Two segments of a dendrite (cell 5 in Fig. 2A) are shown at low power. The axon of cell 3 (of Fig. 2) climbs along the dendrite and establishes seven contacts (b1-7) with it, via club-like (b1-4) and ``en passant'' (b5-7) terminals. C, Low-power electron micrograph of the dendritic segment shown in A, demonstrating the contacts formed by boutons b1 and b3. D, The same dendritic segment from another section with bouton b2. E-H, Boutons 1, 2, and 4-7 are shown at higher magnification to form symmetrical synapses (arrows) on the same postsynaptic dendrite (cell 5). The synaptic cleft is not visible in the case of b7 in this section but has been confirmed by goniometer. The accumulation of gold particles in the presynaptic axons and the postsynaptic dendrites clearly indicate their GABA immunoreactivity. However, because of the masking effect of the pre-embedding CR-immunoreaction endproduct, the GABA immunoreactivity is weaker in these elements than in unstained profiles (see Figs. 5, 6). Scale bars: A, B, 10 µm; C, D, 1 µm; E, 0.5 µm; F, G, 0.25 µm.
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CR-IR axons can be seen in all layers running in all directions, with the radial orientation dominating. The density of axons at the CA1 stratum oriens/alveus border increases, and the axons turn into the horizontal direction. The good quality of axonal staining allowed us to reconstruct relatively long segments of the axonal arborization of CR-IR cells (Fig. 2A,B, from a series of six sections). The morphology of the partially reconstructed axons arising from identified cells was rather variable. Long, rarely branching segments bearing ``en passant'' boutons were interspersed with frequently bifurcating branches, which often formed several club-like terminals (see, for example, the axon of cell 4 in Fig. 2A). The distribution of boutons was rather uneven, 10-30 µm long bouton-free segments were followed by highly varicose portions (because of limits of resolution of photographical reproductions the majority of boutons were omitted, leaving only some to demonstrate the inhomogeneous nature of the axons). Axon collaterals of CR-IR cells often formed close appositions (sometimes axonal baskets) around CR-negative somata outside the principal cell layers (see cell 2 in Fig. 2A).
Fig. 2. Types of connections established by CR-IR cells. A, B, Camera lucida drawing of CR-containing inhibitory interneurons from the CA1 area (2-3 in A) and the dentate gyrus (1 in B). Cell bodies and dendrites are drawn in black; axons are drawn in red. The cells were reconstructed from six consecutive, 80-µm-thick sections. A characteristic property of these cells is that they often form dendro-dendritic and axo-dendritic contacts with each other. Contacting dendrites are shown in the drawings by dotted outlines. Multiple or single arrowheads indicate points where the dendrites ran parallel in close contact, or just touched each other once. An average cell forms dendro-dendritic contact with the dendritic tree of three to seven other CR-IR neurons. Axo-dendritic contacts on cells 1-4 are labeled with arrows. The number of contacts from different CR-IR axons varies between 2 and 10. In many cases, the same axon forms two or more contacts on the same dendrite. The axon of cell 3 formed multiple contacts (3 and 4, open arrows) on the CR-IR dendrite labeled 5. Note that the same two cells formed dendro-dendritic contacts as well. The axon of cell 2 formed a perisomatic basket around a CR-negative cell body in stratum radiatum (open arrows). Because of the limit of photographical reproduction, the axon had to be drawn thicker, and some boutons had to be omitted for the sake of clarity when preparing the illustration. C, Dendro-dendritic connections of a cluster of 15 CR-IR neurons. In the diagram, the cell bodies are represented by circles at their appropriate location within the section. Only those dendritic branches are indicated (simple lines), which contacted other dendrites. Multiple or single dendro-dendritic contacts are indicated by parallel red lines or by red crosses, respectively. Dashed circles are attached to those dendrites that ran out of the series of sections. D, The same cluster represented in a graph form. Double and single lines indicate multiple and single contacts. Reconstruction of the cluster was started from cell 5. Neurons whose entire dendritic tree was checked for contacts are labeled by stars. Open circles indicate those cells in which some of the dendrites (or even the soma) were missing from the series of six sections. This means that the size of an intact cluster can be much larger than 15. E-G, CR-IR axons (black) innervate, via multiple contacts (arrowheads), calbindin D28k-containing interneurons (E, G), as well as VIP-immunoreactive basket cells (F). Scale bars: A, C, 200 µm; E-G, 10 µm.
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Numerous dendro-dendritic and axo-dendritic contacts are formed among CR-IR cells
A remarkable feature of CR-IR cells was that they often formed dendro-dendritic and axo-dendritic contacts with other CR-IR neurons. These contacts were most abundant in the CA1 region (Fig. 2A, cells 2-4; Fig. 1) but could be found regularly in the dentate gyrus (cell 1 on Fig. 2B) and in the CA3 subfield as well. We examined 70 cells in a single section from the CA1 area and found that all of them (70) were involved in at least one (but usually more) axo-dendritic contacts. Dendro-dendritic contacts were somewhat less numerous, but even in this case 61 of the 70 examined cells were in dendro-dendritic contact with at least one other cell in the section examined. A 250-µm-wide radial column of the CA1 area in an 80-µm-thick section contains ~8-12 CR-IR cells scattered in all layers (Fig. 1). As demonstrated in the figure, within such a small area several dendro-dendritic contacts can be seen. Ascending and descending dendrites run in close apposition (arrowheads in Fig. 1B,D,F,G) often for over a 100 µm (see the two dendrites in C) or form a contact limited to one spot. To estimate the number of dendro-dendritic contacts established by a single cell, we reconstructed the dendritic arbor from six 80-µm-thick consecutive sections and drew all the contacts formed with other CR-IR profiles. In most cases three to seven contacts were found (of which one to three were multiple) with other CR-IR dendrites. Because five to six cells interconnected by dendro-dendritic appositions were often seen in a single section, we tried to estimate the extent of such clusters by reconstructing the dendritic arbors of all those cells. One such cluster is demonstrated in Figure 2, C and D. Cell 5 (the outline of one of its dendrites is shown in Fig. 2A) was drawn first, and the cluster was extended by reconstructing contacted cells followed by those they contacted, recursively. The cluster shown consisted of 15 cells connected by multiple and single dendro-dendritic contacts. Another cluster, containing 13 cells (not shown here), was also reconstructed. However, we used only a series of six sections for the reconstruction; therefore, some of the dendritic trees are incomplete. Thus, the number of cells participating in a dendro-dendritically connected cluster is probably underestimated.The frequency of axo-dendritic contacts between CR-IR cells is also illustrated in Figures 1 and 2, A and B. The primarily radially running axons form multiple contacts with dendrites (Fig. 1B,D-G; see also in Figs. 2A, 4) and/or somata (up to 20 boutons) of other CR-IR neurons. A cell can be innervated by 2-10 different CR-IR collaterals, many of them providing multiple contacts. We found examples when both dendro-dendritic and axo-dendritic contacts were formed between two CR-IR neurons (e.g., as between cell 3 and dendrite 5 in Fig. 2A).
Ultrastructure of dendro-dendritic contacts
To reveal the fine structure of dendro-dendritic contacts, areas containing closely apposed dendrites were selected, re-embedded (from the CA1 region and the DG) and serially sectioned for electron microscopy. Examination of several of these dendritic segments demonstrated that numerous regularly spaced zonula adherentia interlock the touching dendrites (Fig. 3A,C,D, arrowheads). This type of membrane specialization is characterized by a thick (25-30 nm) dense projection on both membranes intracellularly, and dense material is present also in the subjunctional extracellular space, which has dimensions similar to those of a synaptic cleft. Vesicles are never found to accumulate near these junctions. The zonula adherentia are positioned at 5-10 µm from each other and can be invariably found where the membranes of two dendrites first join and before they separate, as if they served as a clip to attach the dendrites. Tens of micrometers of dendro-dendritic contacts were thoroughly examined in serial sections in search for gap junctions. However, because of the strong immunoreactivity in both of the contacting dendrites the preservation of the membrane was insufficient for an unequivocal demonstration of this fine membrane specialization. Although in some cases we found contacts resembling gap junctions (Fig. 3B, double arrowheads), they were distorted by the immunoreaction endproduct. Thus, their presence and frequency of occurrence between CR-IR dendrites need to be further investigated. Besides the zonula adherentia, we often found CR-IR axon terminals intercalated between the contacting dendrites and forming symmetrical synapses on one or both of them (Fig. 3C,D, arrow). Such intercalated contacts were mostly located in the proximity of zonula adherentia.
Fig. 3. Ultrastructure of dendro-dendritic contacts between CR-IR dendrites. In A, C, and D, zonula adherentia (arrowheads) are formed between the contacting dendrites. In C and D, one of the CR-IR dendrites receives an additional axo-dendritic contact (white arrow, symmetrical synapse), next to the punctum adherens, from CR-IR axon terminals. The dendrites also receive asymmetrical synapses from unlabeled terminals (curved white and black arrow in A). The membrane segments labeled with double arrowheads in B appear to form a gap junction. However, because of the diamino-benzidine precipitate on the membranes, the type of the specialization is equivocal. Scale bars: A, B, 0.5 µm; C, D, 0.25 µm.
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Multiple symmetrical synapses are formed between identified CR-IR axons and dendrites
CR-IR axons involved in forming axo-dendritic contacts were often traced back to other CR-IR interneurons (see Fig. 2A, cell 3). The cell that gave rise to the axon was often located in different layers than the target neuron, that is, distant pairs of cells such as stratum oriens/stratum radiatum or stratum pyramidale/stratum lacunosum-moleculare pairs were common.The multiple contacts formed between the axon of cell 3 and dendrite 5 (in Fig. 2A) was serially sectioned for electron microscopy to examine the presence of synapses. All the seven terminals established symmetrical synapses on the postsynaptic dendrite (Fig. 4). The presence of gold particles in the axon and the postsynaptic dendrite indicated that they were both immunoreactive for GABA. Boutons 1-4 were located at the end of short side branches of the axon (club-like terminals, similar to long pyramidal cell dendritic spines), whereas boutons 5-7 were ``en passant'' terminals asymmetrically positioned on the main axon, with a bias toward the postsynaptic dendrite. Thus, the axon appears as if it were ``reaching'' toward the postsynaptic dendrite. Besides the CR-containing axon terminals, several other boutons were found to establish further symmetrical and asymmetrical synapses on the CR-IR dendrites.
CR-IR axon terminals selectively innervate GABAergic neurons
To obtain unbiased data for the distribution of postsynaptic targets of identified CR-IR cells, bouton-rich segments of the axonal arbors of cells (cells 1-3 in Fig. 2) from the dentate gyrus and CA1 area were serially sectioned for electron microscopy and postembedding GABA immunogold reaction. The 45 identified axon terminals formed symmetrical synapses on dendrites with medium diameter (Fig. 5). All except one postsynaptic dendrites proved to be GABA-positive, the remaining one was unidentified because of inconsistent GABA labeling in serial sections. In long section series it became evident that the reconstructed CR-IR axons were climbing along the GABAergic dendrites, and placed multiple (at least two to four) synapses onto the same shaft (Fig. 5A-D). The postsynaptic dendrites received further symmetrical (GABA positive) and asymmetrical (GABA negative) synapses from unlabeled axon terminals as well.
Fig. 5. GABAergic dendrites are the postsynaptic targets of CR-IR axon terminals in the CA1 and CA3 subfield. A, Three boutons (b1-3) of cell 2 (of Fig. 2) are shown in the light micrograph. B-D, Examination of the three boutons in the electron microscope revealed that they contact the same GABA-positive postsynaptic dendrite. As shown in the two consecutive sections of boutons 1 and 2 (B, C) and of bouton 3 (D), the CR-IR axon terminals formed symmetrical synapses (arrows) with the GABA-containing dendrite (dG). E, F, GABA-positive axon terminal of cell 1 in Figure 2B. The CR-containing axon is shown in two consecutive sections, forming a symmetrical synapse (arrow) on a GABA-positive dendrite (dG) in stratum moleculare. Asterisks and a star mark GABA-negative and GABA-positive elements in the neuropil. Scale bars: A, 10 µm; B-F, 0.5 µm.
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We also examined 17 randomly selected boutons from the outer molecular layer of the dentate gyrus and from stratum radiatum of the CA1 subfield. These terminals, similarly to the identified ones, terminated solely on GABAergic dendrites, often participating in multiple contacts.
CB-, CR-, and VIP-immunoreactive interneurons are heavily innervated by CR-IR axons
GABAergic interneurons can be subdivided into several functionally distinct subpopulations on the basis of their input-output features, which correlate well with neurochemical characteristics. It is of importance whether CR-IR cells distinguish among these subpopulations of interneurons or they innervate GABAergic neurons of any type. This question was investigated by double-immunostaining for CR (Ni/DAB, black), and the markers of various interneuron subpopulations, that is, CB, PV, CCK, and VIP. The distribution and morphology of the above cell types has been described already in several earlier studies; therefore, only a brief description is given here.CB-IR interneurons (Celio, 1990
The distribution and types of VIP-IR neurons have also been described elsewhere (Köhler, 1982
PV-IR neurons can be found in large numbers in the principal cell layers of all hippocampal regions (Kosaka et al., 1987
CCK-positive cells have a medium-to-large soma, and bitufted dendritic tree in all subfields and layers of the hippocampus. The vast majority have an axon arborizing in stratum pyramidale (basket cells, also containing VIP), whereas a smaller proportion has a sparse arbor in stratum radiatum and oriens (Kosaka et al., 1985
In the CA1 and CA3 regions, where numerous CB-IR interneurons could be reliably examined, CR-IR axon collaterals were found to heavily innervate the CB-IR cells (Fig. 2E,G). From the 142 CB-IR cells found in 11 sections of CA1 area, 131 received multiple contacts from CR-IR axons, which crept along the dendrites and somata of the target neurons, and formed 15-30 terminals (arrowheads in Fig. 2E,G) on them. In contrast to CB-IR interneurons, dendrites or somata of CB-containing pyramidal cells were avoided by CR-IR boutons in the CA1 region. In CA3 46 CB-IR neurons out of 52 examined were innervated by multiple CR-IR axon terminals. CB-IR cells, which did not receive such innervation from CR-IR axons, were mainly located in stratum oriens in both cases.
The basket type of VIP-IR cells, that is, those with large somata, and axons surrounding pyramidal cell bodies, were also heavily innervated by CR-IR axons (Fig. 2F). All of the 68 identified VIP-IR basket cells (50 in the CA1 and 18 in the CA3 region, detected in 10 sections) were densely covered by terminals of CR-IR axons (23-68 boutons per cell). A smaller number of VIP-IR cells with oriens/alveus projection were also innervated by climbing fiber-like CR-IR axons. This was expected because these cells are known to also contain CR. In the dentate gyrus the innervation of VIP-IR basket cells was much less pronounced (only two to three boutons per cell). In Ammon's horn, CCK-IR basket cells were also covered by CR-IR axon terminals, confirming the results of VIP-CR double staining concerning VIP-containing basket cells, because VIP and CCK are known to coexist in this basket cell population (Acsády et al., 1995a).
The contacts between CR-IR axons and neurochemically identified target cells were confirmed to be synapses by correlated electron microscopy. This is illustrated by a VIP-IR basket cell shown in Figures 2F and 6, which received 34 terminals from an identified CR-IR axon. Seven of the terminals were serially sectioned for electron microscopy, and all of them proved to form symmetrical synapses (Fig. 6).
Fig. 6. Light and electron microscopic demonstration of multiple contacts between CR-IR axons and a VIP-IR basket cell. Four of the numerous (n = 34) CR-IR axon terminals (b1-4 in A and B, labeled by dense DAB/Ni precipitate) are shown to form symmetrical synapses in the perisomatic region of a VIP-IR basket cell (outlined by the weaker DAB precipitate). The cell was located at the stratum pyramidale/stratum oriens border (the same cell is shown in Fig. 2F in color). Invaginations on the nuclear membrane (arrows in B) are characteristic features of GABAergic interneurons. The high-power electron micrographs in C and D show two symmetrical synapses (arrows) formed by boutons b1 and b2 in nearby sections. Scale bars: A, 10 µm; B, 1 µm; C, D, 0.5 µm.
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In contrast to the strong innervation of the above cell types, PV-IR cells were largely avoided by the CR-IR terminals in all areas of the hippocampus. If occasional contacts were found, they were all made by single terminals. This conclusion is based on a thorough examination of 16 sections from two animals, which contained several hundred PV-IR neurons and good quality axonal staining for CR.
Termination pattern of CR-IR fibers in stratum lacunosum-moleculare
A large number of CR-IR axons could also be found in stratum lacunosum-moleculare of the CA3 and CA1 subfields. However, the number of terminal varicosities formed in this layer was lower than in other layers. The majority of the axons ran in parallel bundles, and had no terminal varicosities.The postsynaptic targets of axons in this layer were also studied in the electron microscope. CR-IR profiles with axonal morphology (n = 60) were of three types. Axons of the first and second group formed synapses with dendrites, and accounted for a third of CR-IR profiles observed in single sections. Axons of the first group formed symmetrical synapses on GABA-positive dendrites (Fig. 7A,B, n = 9, 15% of all examined elements), whereas terminals of the second targeted GABA-negative dendrites, and formed asymmetrical synapses with characteristically pronounced postsynaptic densities (Fig. 7C,D, n = 11, 18.3%). The majority of the axonal profiles (n = 40, 66.7%), forming the third group, were nonvaricose, contained no synaptic vesicles, and were often myelinated (axons labeled with arrowhead and curved arrow in Fig. 7E).
Fig. 7. Targets of unidentified CR-IR axons in stratum lacunosum-moleculare of the CA1 subfield. In this area, a majority of immunoreactive axonal profiles were either myelinated (curved arrows in E) or were preterminal axons (arrowheads in E), without terminal enlargement. When CR-IR axons formed synaptic varicosities (~30% of the profiles), two types of terminals could be distinguished (~15-15%). In half of the cases, GABA-positive presynaptic boutons formed symmetrical synapses (arrows in A and B) on GABA-positive dendrites (dG). In the other half of the cases, GABA-negative CR-positive terminals formed characteristic asymmetrical synapses with pronounced postsynaptic densities (arrows in C and D) on GABA-negative pyramidal cell dendrites (dP). The ultrastructure of these synapses was similar to those formed by the CR-containing terminals originating from the nucleus reuniens thalami. Scale bars: A-D, 0.5 µm; E, 1 µm.
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DISCUSSION
The major findings of the present study are the following. (1) CR-IR neurons form large dendro-dendritically and axo-dendritically connected clusters. The dendritic braids are held together by regularly spaced zonula adherentia, whereas the dendrites receive multiple symmetrical synapses from several other CR-IR neurons, often from members of the same cluster. (2) CR-IR cells show a high degree of target selectivity; they innervate mostly if not exclusively other GABAergic neurons via multiple synapses. The innervated subclassesOrigin and light microscopy of CR-IR axons
The antiserum used here visualized the dendritic and axonal arbor of CR-IR cells in more detail than the one in our earlier report (Gulyás et al., 1992We could demonstrate that
Irregular distribution of boutons, the presence of club-like terminals, and the asymmetrically positioned ``en passant'' terminals are characteristic features of the intrinsic CR-IR axons. Other groups of inhibitory cells terminating primarily on principal cell dendrites, such as CB-IR cells, SOM-IR cells, and most of those visualized by intracellular filling (Gulyás et al., 1993a
CR-IR axons of extrinsic origin were identified in the dentate gyrus at the stratum granulosum/moleculare border and in strata pyramidale and oriens of the CA2-CA3a border. These axons arise from the supramammillary nucleus both in the rat (Maglóczky et al., 1994
Inhibitory control of interneurons terminating in different soma-dendritic domains of principal cells
GABAergic input onto hippocampal interneurons from intrinsic (Nunzi et al., 1985Here we demonstrated that hippocampal CR-IR interneurons terminate exclusively on interneurons (involving CR-IR cells themselves) forming multiple contacts. Using double immunocytochemistry, the target interneuron subpopulations were also identified. CB-IR interneurons and VIP(CCK)-IR basket cells were the predominant targets of CR-IR axons. CB-containing inhibitory cells were shown to innervate the middle and distal segments of principal cell dendrites both in the hippocampus (Gulyás and Freund, unpublished observations) and the neocortex (DeFelipe et al., 1989
In the study of Acsády et al. (1995a,b), two further subpopulations of VIP-IR interneurons were identified with selectivity for GABAergic neurons. One group of cells were shown to be immunoreactive also for CR, and innervated the somata and horizontally running dendrites of cells located at the stratum oriens/alveus border. The majority of these horizontal cells are immunoreactive both for metabotropic glutamate receptor 1a (mGluR1a) and SOM (Baude et al., 1993
We conclude that CR-IR cells innervate at least three distinct interneuron populations, which terminate in different soma-dendritic domains of principal cells: VIP(CCK)-IR basket cells, CB-IR cells, and SOM-IR cells, which terminate in the perisomatic, in the mid-distal dendritic and in the distal apical dendritic regions, respectively (see Fig. 8).
Fig. 8. Hippocampal microcircuits consist of three major components: (1) the principal cells (gray cells) account for the majority of cortical cells and form long-range as well as local, excitatory connections; (2) diverse groups of inhibitory cells (different hatching), which control the activity of principal cells by exerting inhibition on different somato-dendritic domains; and (3) ``disinhibitory'' neurons (open cells). The CR-IR ``disinhibitory'' neurons are massively interconnected by dendro-dendritic (parallel bars on their dendrites) and axo-dendritic contacts with each other. As a result of mutual synaptic interconnection and dendritic coupling, the activity of these neurons is likely to become rhythmic and synchronized. This oscillation is then conveyed to large populations of pyramidal cells via different inhibitory cell populations. Both dendritic (CB-IR cells) and perisomatic (VIP/CCK-IR cells) inhibition of principal cells may be synchronized in this manner. It is important to note here that, for the sake of clarity, several components of the hippocampal inhibitory circuitry have been ignored to obtain this diagram, which is intended to summarize the present findings. Other subsets of inhibitory cells (e.g., conventional basket cells) are also known to provide input to interneurons, although their major targets remain pyramidal cells. CR, Calretinin; CB, calbindin D28k.
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Cerebral cortical networks were thought to consist of two basic components: (1) a profusely interconnected ensemble of principal cells that accounts for the majority of cortical neurons, and (2) diverse groups of interneurons that control the firing and afferent input of principal cells by exerting inhibition in different soma-dendritic domains (Han et al., 1993
Mutual inhibition and dendro-dendritic connectivity of CR-IR cells may generate synchronous rhythmic activity
A unique feature of CR-IR cells is their extensive interconnectivity. The long dendro-dendritic junctions may be the result of development from common ancestor cells, and during radial migration their dendrites may remain connected. However, the observations that dendro-dendritic contacts can be found between horizontally distant cells and that these contacts are rarely seen until postnatal day 9-10 (L. Acsády, personal communication) argue against this interpretation. The second observation implies that the dendrites of the cells find each other actively during development. A similar active mechanism might explain the precise connectivity of the axons as well.The possible functional role of this extensive interconnectivity is a puzzling question. Several modeling studies demonstrated that mutual inhibition among pairs or clusters of inhibitory neurons may result in rhythmic inhibitory cell activity (Perkel and Mulloney, 1974
Mutually connected inhibitory neurons are thought to be responsible for rhythm generation in the nucleus reticularis thalami (Montero and Singer, 1984
The importance of rhythmic, synchronous cortical activity has been recently emphasized in connection with feature binding and temporal coding (Gray et al., 1990
FOOTNOTES
Received Dec. 6, 1995; revised Feb. 20, 1996; accepted Feb. 23, 1996.
This work was supported by the Human Frontier Science Program Organization, The Howard Hughes Medical Institute, and OTKA (No. T 5532, T 16942) Hungary. We are grateful to Dr. J. H. Rogers for the antiserum against calretinin, to Dr. T. Görcs for antisera against VIP and CCK, to Dr. K. G. Baimbridge for anti-parvalbumin and anti-calbindin, and to Dr. P. Somogyi for the anti-GABA serum. The excellent technical assistance of Mrs. E. Borók, Mrs. A. Z. Szabóné, and Mr. G. Terstyánszky is also acknowledged.
Correspondence should be addressed to Tamás F. Freund, Institute of Experimental Medicine, Hungarian Academy of Sciences, P.O. Box 67, Budapest H-1450, Hungary.
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