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The Journal of Neuroscience, February 15, 2000, 20(4):1519-1528
Gap Junctions Linking the Dendritic Network of GABAergic
Interneurons in the Hippocampus
Takaichi
Fukuda and
Toshio
Kosaka
Department of Anatomy and Neurobiology, Graduate School of Medical
Sciences, Kyushu University, Fukuoka 812-8582, Japan
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ABSTRACT |
The network of GABAergic interneurons connected by chemical
synapses is a candidate for the generator of synchronized oscillations in the hippocampus. We present evidence that parvalbumin
(PV)-containing GABAergic neurons in the rat hippocampal CA1 region,
known to form a network by mutual synaptic contacts, also form another network connected by dendrodendritic gap junctions. Distal dendrites of
PV neurons run parallel to the alveus (hippocampal white matter) and
establish multiple contacts with one another at the border between the
stratum oriens and the alveus. In electron microscopic serial section
analysis, gap junctions could be identified clearly at 24% of
these contact sites. A dendrodendritic chemical synapse and a mixed
synapse also were found between PV-immunoreactive dendrites.
Three-dimensional reconstruction of the dendritic arborization revealed
that both PV neurons of the well known vertical type (presumptive
basket cells and axoaxonic cells) and those of another horizontal type
constitute the dendritic network at the light microscopic level. The
extent of dendritic fields of single PV neurons in the lateral
direction was 538 ± 201 µm (n = 5) in the vertical type and 838 ± 159 µm (n = 6) in
the horizontal type. Our previous and present observations indicate
that PV-containing GABAergic neurons in the hippocampus form the dual
networks connected by chemical and electrical synapses located at
axosomatic and dendrodendritic contact sites, respectively. Gap
junctions linking the dendritic network may mediate coherent synaptic
inputs to distant interneurons and thereby facilitate the
synchronization of oscillatory activities generated in the interneuron network.
Key words:
gap junctions; GABA; parvalbumin; hippocampus; electron
microscopy; oscillation; synchronization
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INTRODUCTION |
Recent physiological studies have
revealed large-scale synchronous and oscillatory activities such as
gamma (30-80 Hz) (Singer and Gray, 1995 ; Steriade et al., 1996; Traub
et al., 1998) and sharp wave-associated "ripple" (200 Hz) (Ylinen
et al., 1995) in mammalian brains. These rhythmic activities are
proposed to play important roles in cognition, memory formation, and
other higher nervous functions (Gray et al., 1989; Miltner et al.,
1999; Rodriguez et al., 1999). The mechanisms underlying these rhythms are still uncertain, but cumulative evidence suggests that a
synaptically connected network of GABAergic interneurons is critically
involved in generating the oscillatory activities at least in some
hippocampal (Soltesz and Deschênes, 1993; Michelson and Wong,
1994; Bragin et al., 1995; Whittington et al., 1995; Ylinen et al.,
1995; Traub et al., 1996a) and neocortical (Buhl et al., 1998) cases.
Because single hippocampal inhibitory neurons innervate hundreds of
principal neurons (Somogyi et al., 1983; Sik et al., 1995; Halasy et
al., 1996), oscillations generated in the interneuron network will produce periodic inhibition efficaciously in a large number of targeted
neurons, set their timing of discharge in-phase, and thereby cause
synchronous oscillatory activities in a large population of neurons
(Cobb et al., 1995).
Several physiological (Michelson and Wong, 1994; Ylinen et al., 1995)
and computer simulation (Traub, 1995; Skinner et al., 1999) studies
have suggested that gap junctions between GABAergic interneurons, if
they exist, will facilitate synchronous oscillations. Our previous
ultrastructural studies (Kosaka, 1983a,b; Kosaka and Hama, 1985)
clearly demonstrated that certain types of hippocampal interneurons,
especially those containing a calcium-binding protein parvalbumin (PV)
(Katsumaru et al., 1988b), form gap junctions between their dendrites.
PV neurons correspond to somatic inhibitory interneurons (Kosaka et
al., 1987; Katsumaru et al., 1988a) that target the perisomatic domain
of pyramidal cells and possibly regulate the generation of
Na+-dependent action potentials there
(Knowles and Schwartzkroin, 1981; Buhl et al., 1994a; Miles et al.,
1996). With the use of a particular combination of enzyme isoforms for
GABA synthesis at their synaptic terminals (Fukuda et al., 1998), PV
neurons innervate not only pyramidal cells but other PV neurons as well through dense mutual synaptic contacts on their somata and proximal dendrites (Sik et al., 1995; Fukuda et al., 1996). Accordingly, PV
neurons can form both dendrodendritic gap junctions and a synaptically connected network, supporting the above hypothesis that gap junctions facilitate synchronous oscillations generated in the interneuron network. However, the gap junctional profiles we previously observed were limited to those formed between vertically oriented dendrites arising from nearby neurons [see Kosaka and Hama (1985), their Fig.
12], suggesting synchrony only in a localized circuit; it remains
uncertain how gap junctions are incorporated in a large-scale network
and implicated in the long-range synchrony. The present study aims to
search for an unrecognized network structure linked by gap junctions,
particularly that extends laterally inside the hippocampus, and to
shed light on the functional roles of gap junctions in the neural
system of the hippocampus.
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MATERIALS AND METHODS |
Tissue preparation. Eight male Wistar rats
(200-300 gm, 8-12 weeks old) were used in accordance with the
institutional guidance for animal welfare. Under deep anesthesia with
sodium pentobarbital (10 mg/100 gm body weight, i.p.) the animals were
perfused quickly through the ascending aorta with 300 ml of fixative A
containing 2.5% glutaraldehyde and 2% paraformaldehyde in 0.1 M phosphate buffer (PB) or fixative B containing 4%
paraformaldehyde, 0.1% glutaraldehyde, and 0.2% picric acid in the
same buffer, pH 7.2, at room temperature. After cryoprotection and the
freeze-thaw procedure, serial coronal or tangential sections 40-50
µm in thickness were cut with a Vibratome (Technical Products, St.
Louis, MO). For preparation of tangential sections the hippocampal
formation, together with the overlying neocortex, was removed gently
from the brainstem and cut transversely into three to four blocks. The
surface of the neocortex was glued to the stage, and sectioning was
started from the hippocampal surface that originally had faced the thalamus.
Immunocytochemistry. Sections were processed for
immunocytochemistry with the use of the free-floating method, as
described previously (Fukuda et al., 1996). When fixative A was used,
the sections were treated first with 1% sodium borohydride
(NaBH4) for 30 min before immunocytochemical
procedures (Kosaka et al., 1986). Triton X-100 (0.3%) was used for
confocal laser-scanning microscopy and three-dimensional neuron
tracing, but not for immunoelectron microscopy. The primary antibodies
used were rabbit polyclonal antibody against rat PV (dilution 1:5000;
Kägi et al., 1987), sheep polyclonal antibody S3 (1:2000; Oertel
et al., 1981) that recognizes both isoforms of glutamic acid
decarboxylase, GAD67 and GAD65, and mouse monoclonal antibody against
synaptophysin (1:1000; Obata et al., 1987). For double or triple
immunostaining PV was visualized with fluorescein
isothiocyanate-conjugated donkey anti-rabbit IgG (1:100; Jackson
ImmunoResearch, West Grove, PA), GAD with biotinylated donkey anti-goat
IgG (1:500; Jackson ImmunoResearch) followed by lissamine
rhodamine-conjugated streptavidin (1:200; Jackson
ImmunoResearch), and synaptophysin with Cy5-conjugated donkey
anti-mouse IgG (1:200; Jackson ImmunoResearch).
Confocal laser-scanning microscopy. Sections were mounted in
Vectashield (Vector Laboratories, Burlingame, CA) and examined with
a confocal laser-scanning microscope MRC-1000 (Bio-Rad, Herts, UK)
equipped with a krypton-argon ion laser and mounted on a light microscope (Optiphoto, Nikon, Tokyo, Japan), as described (Fukuda et
al., 1998). For taking images of higher resolution, a 60× oil immersion objective (numerical aperture, 1.40; Nikon) was used at 2×
zoom factor. Single laser beams, 488, 568, and 647 nm in wavelength,
were used alternately to collect images for different fluorescent
signals, and the bleedthrough was confirmed to be negligible by using
the mixer program of the instrument.
Electron microscopy. Vibratome sections (50 µm) from
animals fixed with fixative A were processed for immunocytochemistry as
described (Obata et al., 1999), post-fixed with 1%
OsO4 for 1.5 hr on ice, stained en bloc with
uranyl acetate, dehydrated, and embedded in Araldite. Serial ultrathin
sections 60-70 nm in thickness were cut from the superficial part of
the reembedded specimens, mounted on Formvar-coated single slot grids,
lightly stained with uranyl acetate and lead citrate, and examined in a
transmission electron microscope (Hitachi H-7100, Tokyo, Japan). For
quantitatively analyzing the incidence of gap junctions, two sets of
100 serial ultrathin sections were prepared. Every fifth of the series
was examined thoroughly from the upper left corner to lower right of
each section. For all of the contact sites between PV-ir dendrites that
were encountered, the corresponding profiles in neighboring sections
were observed intensively as far as it could be determined whether a
gap junction was identifiable at the contact site or not. During the
analysis the sample stage was rotated appropriately and then tilted up
to ± 45° to visualize the cut ends of apposed junctional
membranes clearly, because it was found to be absolutely essential for
identifying gap junctions to make the disk-like junctional membranes
parallel to the electron beam. Once the specimens were oriented
optimally, profiles of closely apposed unit membranes became
discernible. When apposed cell membranes were oriented originally
parallel to the section surface (perpendicular to the electron beam),
they could not become oriented parallel to the electron beam even
if the sample stage was tilted maximally; such cases were excluded from
quantitative analysis.
Neuron tracing. Serial coronal or tangential sections from
animals fixed with fixative B were immunostained for PV, colored with
diaminobenzidine tetrahydrochloride, enhanced with
OsO4, and used for three-dimensional
reconstruction of the dendritic arborization with the aid of a
computer-assisted neuron-tracing system NeuroLucida (MicroBrightField,
Colchester, VT). Shrinkage factor was estimated to be 0.80 for coronal
sections and 0.84 for tangential sections, respectively, by comparing
the size of several sections measured before and after the staining
procedures. Reconstructed figures were viewed from different angles by
the application software NeuroExplorer (MicroBrightField).
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RESULTS |
Dendritic network of PV neurons revealed by tangentially
oriented slices
In usual coronal or sagittal sections the somata of PV-containing
neurons are observed mainly in and around the pyramidal cell layer
(Fig. 1a) with their dendrites
spanning all hippocampal layers, giving each neuron a vertical
appearance (Fig. 1b). Double immunofluorescently stained
sections show that PV neurons establish GABAergic synaptic contacts
with somata of both pyramidal cells and other PV neurons (Fig.
1c,d), indicating mutual perisomatic synaptic
contacts between PV neurons just as observed in the mouse hippocampus
(Fukuda et al., 1996). To reveal a structure that extends laterally
inside the hippocampus, we prepared a series of sections cut
tangentially to the alveus (hippocampal white matter). In such series
we found a dense network of PV-immunoreactive (-ir) dendrites in the
most basal part of the hippocampus proper (Fig.
2a), i.e., at the border
between the stratum oriens and the alveus. Numerous PV-ir dendrites
spread out within a single 40-µm-thick tangential section, meaning
that they were oriented almost two-dimensionally and parallel to the
cutting direction, namely to the alveus.
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Figure 1.
Morphological characteristics of PV neurons viewed
in conventionally oriented coronal sections. a, A
montage of confocal laser-scanning microscopic images. Somata of PV
neurons are located mainly in and around the pyramidal cell layer
(P) and the granule cell layer
(G). Their axon terminals also are distributed in
the same layers, causing band-like staining in lower magnification.
b, PV neurons in the pyramidal cell layer of the CA1
region give rise to dendrites spanning all hippocampal layers.
A, Alveus; O, stratum oriens;
R, stratum radiatum; Lm, stratum
lacunosum-moleculare. c, d, Double
immunostaining with antibodies against PV (c) and
GAD (d). Note multiple PV-containing
GAD-immunoreactive (ir) boutons (arrows) abutting on the
PV-ir soma. Arrowheads indicate similarly double-labeled
boutons, some of which may abut on unstained somata of pyramidal
neurons. Scale bars: a, 0.5 mm; b, 50 µm; c, d, 5 µm.
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Figure 2.
CLSM images in a section cut tangentially along
the border between the alveus and the stratum oriens of the CA1 region.
a, PV-ir dendrites running two-dimensionally within a
single 40-µm-thick section form an extremely dense network. Some
dendrites appear to be bundled together (open arrows),
whereas others cross one another with a fairly wide angle. Four PV-ir
somata are of the horizontal type (see Results). b,
Stereo pair of the enlargement of the framed area in
a. PV-ir dendrites make multiple contacts with one
another, only three of which are indicated by arrows.
c-e, Single confocal optical images of the three
contact sites designated in b, suggesting a direct
contact between these dendrites. Scale bars: a, 50 µm;
b-e, 1 µm.
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In the high-resolution confocal laser-scanning microscopy (CLSM), PV-ir
dendrites in the network appeared to make multiple contacts with one
another. This is illustrated in both the stereo-paired (Fig.
2b) and single confocal images (Fig.
2c-e). Such a dense network of PV-ir dendrites
with possible mutual contact sites was not a rare profile but was seen
ubiquitously all along the border between the stratum oriens and the
alveus in the entire CA1 region from the septal to temporal end of the hippocampus.
Ultrastructural identification of gap junctions
We further investigated by electron microscopy whether these
presumable contact sites really have some specialized ultrastructures (Fig. 3). PV-ir dendrites in the
oriens/alveus border frequently made direct contact with other PV-ir
dendrites (Fig. 3a, f, h), and in some
cases gap junctions could be identified there clearly (Fig.
3b, g, i). Characteristic profiles of
neuronal gap junctions were confirmed in more detail by observing
similar dendritic contacts in specimens not treated for immunostaining
(Fig. 3c-e). The outer leaflets of plasma
membranes of the two contacting dendrites were closely apposed, with a
narrow gap between them (Fig. 3e), although in immunolabeled
specimens the gap usually was occluded with dense materials, perhaps
the immunoreaction products. Another characteristic feature of neuronal
gap junctions was a semidense material undercoating the junctional
membranes (Fig. 3d, g, i), which was
not observed in glial gap junctions (Sotelo and Korn, 1978).
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Figure 3.
Electron micrographs showing the dendrodendritic
gap junctions. a, Two PV-ir dendrites
(D) receiving multiple presynaptic terminals
(asterisks) make direct contact with each
other. b, Enlargement of the contact site in
a. A gap junction is formed between the two PV-ir
dendrites. Note the close apposition of the plasma membranes of the two
contacting cells as demarcated by arrows. A synaptic
bouton (asterisk) forming a synapse of asymmetrical type
is located in close vicinity to the gap junction. c,
Electron micrograph of a specimen without immunoreaction, demonstrating
a profile similar to a. The contacting dendrites
(D) receive presynaptic terminals
(asterisks). d, Enlargement of
the contact site in c with the same magnification as in
b, g, and i to facilitate
comparison. Plasma membranes of the two cells are closely apposed, as
demarcated by arrows. Note a layer of cytoplasmic
semidense material (arrowheads) undercoating either side
of the junction, which is characteristic of neuronal gap junctions.
e, Further enlargement of the contact site in
d, showing a narrow central gap, 2.7 nm wide, between
the outer leaflets of the apposed unit membranes. f-i,
Other examples of gap junctions formed between PV-ir dendrites
(D). The contact sites in f and
h are enlarged in g and i,
respectively, with the same magnification as in b and
d. Scale bars: a, c,
f, h, 1 µm; b,
d, e, g, i,
0.1 µm.
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Although unambiguous profiles of gap junctions were encountered
repeatedly, careful examination revealed that gap junctions were not
always formed between directly contacting dendrites of PV neurons. So
we tried to evaluate the incidence of gap junctions between PV-ir
dendrites by systematically and quantitatively observing all of the
contact sites located in two series of 100 consecutive ultrathin
sections. Six contact sites (24%) of 25, including one in the mixed
synapse (see below), could be identified convincingly as gap junctions,
whereas eight contact sites showed no specialization, one site formed
dendrodendritic chemical synapse (see below), and the remaining 10 sites showed ambiguous profiles that were obscured by dense
immunoreaction products. It was concluded that at least a quarter of
contact sites between PV-ir dendrites at the oriens/alveus border
formed gap junctions. In contrast to the frequent occurrence of gap
junctions between PV-ir dendrites, we encountered no gap junctions
between PV-negative neuronal profiles, although we did not observe them
systematically and therefore might have underestimated the latter.
In the course of the serial section analysis, two novel types of
connections were observed between PV-ir dendrites. One was a
dendrodendritic synapse (n = 1 of 25 contact sites;
Fig. 4a), and the other was a
mixed synapse establishing both a chemical synapse and a gap junction
side by side (n = 1 of 25 contact sites; Fig.
4b,c). By observing neighboring consecutive
sections, we found that in each case synaptic vesicles were
located only in one side of the synaptic connections; i.e., neither of
these two contacts formed reciprocal synapses. The existence of the
dendrodendritic synaptic contact indicates that dendrites of PV neurons
can communicate occasionally with each other via chemical synapses.
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Figure 4.
Electron micrographs showing two novel forms of
dendrodendritic contacts between PV neurons. a, Two
PV-ir dendrites (D) receiving multiple
presynaptic terminals (asterisks) make direct contact
with each other (arrow). Inset,
Enlargement of the contact site demonstrating synaptic vesicles,
widening of the synaptic cleft, and less prominent thickening of the
postsynaptic density; the last feature is consistent to conventional
symmetrical synapses, including those formed by PV-ir axon terminals.
b, c, Serial ultrathin sections with
different magnifications demonstrating that two PV-ir dendrites
(D), receiving multiple presynaptic terminals
(data not shown in these sections), establish a mixed type of synapse
between each other. Synaptic vesicles (Sv) accumulate in
one side of the contact as in a, but in this case the
gap junction can be identified in line with the chemical synapse in
c. Note a layer of cytoplasmic semidense material
(arrows) undercoating gap junction as in Fig.
3d, g, i. Scale bars:
a, b, 1 µm; Inset in
a, c, 0.1 µm.
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PV-ir dendritic membranes received multiple synaptic contacts, most of
which were of the asymmetrical type (see Fig. 3). This was in good
accordance with CLSM observations of the triple-immunostained sections
(see Fig. 6a) showing that PV-ir dendrites are surrounded by
numerous synaptophysin-positive/glutamic acid decarboxylase (GAD)-negative boutons, a majority of which are thought to correspond to boutons making asymmetrical synapses (see Fig. 3a).
Although no physiological data are available now, this ultrastructural arrangement leads us to speculate that the changes in postsynaptic membrane potentials in PV-ir dendrites, at least those induced by
synaptic inputs near gap junctions, may be transmitted directly from
one dendrite to another through gap junctions.
Three-dimensional reconstruction of the PV neurons that constitute
the network
Finally, we examined the origins of the dendrites forming the
network. We made a detailed three-dimensional analysis of the dendritic
arborization by using a computer-assisted neuron tracing system (Fig.
5). In specimens prepared for
immunoelectron microscopy, the permeation of antibodies into sections
was restricted greatly, and only short segments of dendrites located
near the section surface were immunostained. Therefore, it was very
difficult to trace dendrites from the sites of ultrastructurally
identified gap junctions all the way back to their parent somata in our
trials of the correlated light and electron microscopy. The following analysis was based on light microscopic observations and our intent to
know the possible constituents of the dendritic network.
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Figure 5.
Comparison of the reconstructed dendritic
arborization of PV neurons between the vertical type
(left) and the horizontal type (right),
viewed in two directions (top, top view;
down, front view) with the use of a computer-assisted
neuron tracing system. The top and front views are of the same cell in
each type and are aligned.
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Dendrites arising from PV neurons of the well known vertical type, the
somata of which were located in and around the pyramidal cell layer,
were followed in serial coronal sections. It was found that
all of the basal dendrites ran obliquely in the stratum oriens (see
Figs. 1b, 5, 6b), gradually changed direction
more horizontally before reaching the oriens/alveus border, and finally
became oriented almost parallel to the alveus, joining the network
there (Fig. 5, left panel). Dendrodendritic contacts
often were observed along the horizontal part of the dendrites. By
viewing the reconstructed dendritic trees from the top side just as if
they had been viewed in tangential sections, we estimated the size of
the dendritic field of these conventional PV neurons along the
oriens/alveus border to be 538 ± 201 µm (n = 5;
ranging from 377 to 875 µm) in the largest diameter.
Besides the above-mentioned vertical type, we noted PV neurons of a
horizontal type, which have not been well described previously (Katsumaru et al., 1988a). They were located in the stratum oriens, most frequently at the border to the alveus. In coronal sections long
dendrites arising from these cells ran along the alveus (Fig. 6b). In tangential sections
their long dendrites appeared to extend in all directions parallel to
the oriens/alveus border (see Figs. 2a, 6c).
Multiple dendrodendritic contacts were observed along the dendrites,
just as seen in the vertical type. Three-dimensional reconstructions
revealed that the dendritic field of the horizontal PV neurons along
the oriens/alveus border reached 838 ± 159 µm (n = 6; ranging from 689 to 1057 µm) in the largest
diameter (see Fig. 5, right panel). The
reconstructions also showed one or two additional dendrites ascending
into the pyramidal cell layer (see Fig. 5). Some, but not all, of the
horizontal PV neurons received dense PV-ir GABAergic terminals on their
somata and proximal dendrites (Fig. 6d, e), a
feature common to the conventional vertical type (see Fig.
1c, d). Similar profiles also were observed in
animals in which extrinsic septohippocampal PV-ir fibers had been
removed by bilateral transection of the fimbria fornix (our unpublished observations), indicating that at least a part of the PV-ir terminals on the horizontal type is thought to be derived from intrinsic PV
neurons.
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Figure 6.
Top. CLSM images showing several
morphological aspects of PV-ir neurons viewed in tangential
(a, c-e) and coronal
(b) sections. a,
Triple-immunostained section at the border between the stratum oriens
and the alveus. PV-ir dendrites (green) receive
numerous synaptophysin (red)-positive and GAD
(blue)-negative boutons (arrows). The
mutual contact sites in dendrites are shown by
arrowheads. b, A PV neuron of the
horizontal type (arrow) located at the border between
the stratum oriens (O) and the alveus
(A) gives rise to long dendrites
(arrowheads) along the border. The stratum oriens
contains many obliquely running dendrites originating from PV-ir somata
located in and around the stratum pyramidale (P).
c, Dendrites of horizontal PV neurons extend in all
directions from their somata along the horizontal plane.
d, e, Enlargement of the PV-ir neuron,
indicated by an arrow in c,
double-immunostained with antibodies against PV
(green) and GAD (red). CLSM images
in d and e were taken at different depths
from the section surface. Note numerous PV-containing GABAergic boutons
(arrows) abutting on the soma and proximal dendrites.
Scale bars: a, 5 µm; b,
c, 50 µm; d, e, 10 µm.
Figure 7.
Bottom. A schematic drawing representing
the dual networks of hippocampal PV neurons connected by chemical and
electrical synapses. PV neurons are shown in color,
whereas pyramidal cell somata are depicted as gray
ovals. Frequent occurrence of gap junctions between
horizontally oriented dendrites (top of the figure) was
confirmed by quantitative electron microscopic analysis, but it remains
unknown whether both or either of the two neuronal types (vertical and
horizontal) actually forms gap junctions there. See Discussion for
details.
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DISCUSSION |
The findings are summarized schematically in Figure
7. PV-ir GABAergic neurons form a dense
network of horizontally oriented long dendrites that make direct
contact with one another at multiple sites. Both the well known
vertical type, corresponding to somatic inhibitory cells, and another
horizontal type constitute the network. Ultrastructural profiles of gap
junctions could be observed in at least a quarter of the contact sites
in the network, although it remains undetermined how these two neuronal
types are involved in gap junctional coupling (see below). The
dendritic network at the oriens/alveus border appears to be continuous
all along the septotemporal (longitudinal) axis of the hippocampus.
Moreover, PV neurons in the CA3 region also form a dendritic network
similar to and continuous with the network in the CA1 region. Taken
together, it is likely that a large population of PV-ir neurons in the
hippocampus proper forms the dendritic network at both the apical
(Katsumaru et al., 1988b) and basal (present observations) contact
sites. Because PV neurons (Sik et al., 1995; Fukuda et al., 1996) and the corresponding somatic inhibitory neurons (Cobb et al., 1997) also
form a network connected by mutual perisomatic synapses and because the
extent of their axonal fields is similar in size to that of the
dendritic fields shown here (Buhl et al., 1994b; Sik et al., 1995;
Halasy et al., 1996), PV neurons in the hippocampus appear to form the
dual networks mediated by chemical and electrical synapses located at
axosomatic and dendrodendritic contact sites, respectively.
Identification of neuronal gap junctions
In mammalian brains unambiguous ultrastructural evidence for the
existence of neuronal gap junctions has been demonstrated only in very
limited areas (Brightman and Reese, 1969; Pinching and Powell, 1971;
Sloper, 1972; Sotelo et al., 1974; Kosaka and Hama, 1985) (for review,
see Sotelo and Korn, 1978), and works elucidating the functional
significance of neuronal gap junctions are rare (Llinás et al.,
1974; De Zeeuw et al., 1996). In the present study gap junctions could
be observed clearly in immunocytochemically identified neurons by
careful preparation of the specimens, using a high concentration of
glutaraldehyde for fixation, and by detailed electron microscopic
observations. Incidence of gap junctions was estimated further by
serial ultrathin section analysis, and their distribution was
correlated to the large-scale network structure of dendrites that arise
from neurons constituting a potential oscillation generator. Although
we had no physiological data, the present results will provide an
anatomical basis for understanding functional aspects of neuronal gap
junctions in mammalian cortical circuits.
Dendrodendritic chemical synapse and mixed synapse
Two additional types of dendritic contacts, dendrodendritic
chemical synapse and mixed synapse, were noted between PV neurons. Although not described earlier in the hippocampus, similar structures already have been demonstrated between dendrites of nonpyramidal neurons in the neocortex (Sloper, 1972; Sloper and Powell, 1978). Only
one profile was found for each type here, but this might be an
underestimation because immunoreaction products frequently obscured
ultrastructural details. In each type synaptic vesicles accumulated in
dendritic shafts. The localization of presynaptic sites in dendritic
shafts resembles that in mitral cell dendrites in the olfactory bulb
(Rall et al., 1966) but is contrasted with the synaptic glomeruli in
the thalamic nuclei (Rafols and Valverde, 1973) and the gemmules of
granule cells in the olfactory bulb (Price and Powell, 1970); in the
latter two structures spine-like presynaptic sites in the dendrites are
segregated from dendritic shafts by intervening thin necks. Presynaptic
dendrites of mitral cells are activated by spikes propagated along the
dendritic shafts, whereas activation of presynaptic spine-like
structures is thought to result from local excitatory synaptic inputs
inside the segregated structures (Jahr and Nicoll, 1982). Further
physiological studies are needed to determine whether transmitter
release from PV-ir dendritic shafts is induced by possible dendritic
spikes as in mitral cells or by local inputs. As to the dendrodendritic
mixed synapse, although similar profiles were described in the
neocortex (Sloper, 1972; Sloper and Powell, 1978), little is known
about its functional role in vertebrates.
Horizontal PV neurons
PV neurons of a horizontal type were noticed in tangential
sections. Although we could not determine their axonal targets, part of
them may correspond to the "oriens/alveus interneurons" sending
axons in the pyramidal cell layer (Lacaille et al., 1987), because
there is some resemblance between the two populations both in the
dendritic arborization pattern (many horizontal dendrites with
additional one or two ascending processes) and in the axonal ramification pattern in the pyramidal cell layer. Alternatively, they
may belong to so-called O-LM interneurons that selectively innervate the stratum lacunosum-moleculare (McBain et al., 1994; Sik et
al., 1995). However, this does not seem to be the case, because PV-ir
terminals are observed only rarely in that layer. Dense PV-ir boutons
abutting on some horizontal PV neurons suggest another possibility that
some of them innervate one another. Because axons of the vertical type
reconstructed in vivo do not enter the alveus/oriens border
(Sik et al., 1995), PV-ir boutons on the horizontal type appear to be
derived from sources other than the vertical type. In any case, the
fact that some horizontal PV neurons are densely innervated by other PV
neurons suggests that part of this type also joins the GABAergic
network linked by synaptic contacts and might be involved in the
generation of oscillatory/synchronous activity.
Origins of gap junction-forming dendrites
It is important to emphasize that the present ultrastructural
results did not demonstrate directly the parent somata to which gap
junction-coupled dendrites could be traced. This was attributable to
the mutually exclusive experimental conditions; i.e., fair preservation
of tissues was an essential prerequisite to the ultrastructural identification of gap junctions, whereas it greatly reduced the permeation of antibodies, leading to the labeling of only short dendritic segments. On the other hand, dendrodendritic contact sites at
the light microscopic level were located mainly in the distal
dendrites, several hundred micrometers apart from their somata.
Accordingly, it remains unknown whether the dendrodendritic gap
junctions in the oriens/alveus border include junctions only between
vertical cells or between horizontal cells or are between both
horizontal and vertical cells. However, as to the possibility of
junctions between vertical cells, we previously observed gap junctions
between PV-ir vertical dendrites in the stratum radiatum (Katsumaru et
al., 1988b), which correspond most probably to apical dendrites of the
vertical type. This indicates that vertical PV neurons constantly
express proteins to form gap junctions, raising the possibility that
they also form gap junctions between their dendrites elsewhere, e.g.,
near the alveus/oriens border. Because multiple dendrodendritic
contacts also were observed along dendrites of horizontal PV neurons at
the light microscopic level, attempts should be continued to ensure the
existence of dendritic gap junctions in both types of PV neuron and to
establish "the dendrodendritic connectivity" between PV neurons.
Functional implications of gap junction-mediated network
Because transmembrane proteins constructing gap junctions are
permeable to small molecules, gap junctions formed between excitable cells can mediate the electrical coupling of the cells, leading to
synchronous activity of the interconnected cell population. In the
present study gap junctions were found between dendrites of hippocampal
PV neurons. PV neurons form a GABAergic synapse-mediated network with
both pyramidal cells and other PV neurons. This synaptically connected
network has been assumed to be an oscillation generator (Whittington et
al., 1995; Traub et al., 1996a). Recently, it has been shown that
excitatory connections from pyramidal cells to interneurons will
reinforce the synchronous gamma oscillations (Traub et al., 1996b).
Importantly, the border between the stratum oriens and the alveus,
where the gap junction-mediated horizontal dendritic network is
located, is the terminal region of axon collaterals from CA1 pyramidal
neurons. In fact, paired intracellular recordings revealed that single
pyramidal cells elicit EPSPs in postsynaptic interneurons located at
the oriens/alveus border (Lacaille et al., 1987; Ali and Thomson,
1998). Therefore, numerous asymmetrical synapses abutting on PV-ir
horizontal dendrites are thought to be derived mainly from pyramidal
cell axons. If these inputs are transmitted through gap junctions and
are shared as coherent inputs between network-forming PV neurons, they
will greatly facilitate the synchronization of oscillatory activities
generated in the interneuron network. Very recently, simultaneous
recordings from pairs of fast-spiking cells in the neocortex revealed a
high occurrence of electrical coupling among them (Galarreta and
Hestrin, 1999; Gibson et al., 1999). These neurons were reported to be
PV-immunoreactive in most cases and also were interconnected by
GABAergic synapses. Therefore, the dual networks of PV-containing
GABAergic neurons that we found in the hippocampus appear to be common
to several cortical regions.
The large size of dendritic fields (500-800 µm, on average) suggests
that coherent inputs might be shared between PV-ir dendrites arising
from spatially distant somata. This partially may explain the
mechanisms of long-range synchrony observed in vivo.
Moreover, so long as it is considered anatomically, the entire network
of horizontally oriented dendrites that are linked by multiple gap junctions will cover a broader area, several millimeters wide. Interestingly, the present data revealed that some dendrites of PV
neurons have a presynaptic nature in their morphological features (see
Fig. 4). Based on the high probability of synaptic transmission between
presynaptic pyramidal cells and postsynaptic somatic inhibitory neurons
(Gulyás et al., 1993), a computational modeling study (Traub and
Miles, 1995) suggested the occurrence of active propagation of signals
along the dendrites of hippocampal somatic inhibitory neurons. Possible
active conductance along PV-ir dendrites might strengthen the
transmission of coherent signals and reinforce the synchronous activity
in a wider area.
| |
FOOTNOTES |
Received Sept. 24, 1999; revised Nov. 17, 1999; accepted Dec. 3, 1999.
This work was supported by Grants-in-Aid for Exploratory Research
(10878150) to T.F., for Scientific Research on Priority Areas (A)
(11170242) and for Scientific Research (B) (09480213) to T.K., from The
Japanese Ministry of Education, Science, Sports and Culture, and also
by a grant from the Ichiro Kanehara Foundation to T.F. We are grateful
to Drs. Claus W. Heizmann and Shinobu C. Fujita for providing antibodies.
Correspondence should be addressed to Dr. Takaichi Fukuda at the above
address. E-mail: fukuda{at}a3rd.med.kyushu-u.ac.jp.
| |
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In Vivo Labeling of Parvalbumin-Positive Interneurons and Analysis of Electrical Coupling in Identified Neurons
J. Neurosci.,
August 15, 2002;
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[Abstract]
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A. Losonczy, L. Zhang, R. Shigemoto, P. Somogyi, and Z. Nusser
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J. Physiol.,
July 1, 2002;
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C. Wu, H. Shen, W. P. Luk, and L. Zhang
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T. Bem, Y. Le Feuvre, J. Simmers, and P. Meyrand
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R. D. Traub, N. Kopell, A. Bibbig, E. H. Buhl, F. E. N. LeBeau, and M. A. Whittington
Gap Junctions between Interneuron Dendrites Can Enhance Synchrony of Gamma Oscillations in Distributed Networks
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J. H. Singer, R. R. Mirotznik, and M. B. Feller
Potentiation of L-Type Calcium Channels Reveals Nonsynaptic Mechanisms that Correlate Spontaneous Activity in the Developing Mammalian Retina
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M. D. McEchron, A. P. Weible, and J. F. Disterhoft
Aging and Learning-Specific Changes in Single-Neuron Activity in CA1 Hippocampus During Rabbit Trace Eyeblink Conditioning
J Neurophysiol,
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[Abstract]
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K. Oguro, T. Jover, H. Tanaka, Y. Lin, T. Kojima, N. Oguro, S. Y. Grooms, M. V. L. Bennett, and R. S. Zukin
Global Ischemia-Induced Increases in the Gap Junctional Proteins Connexin 32 (Cx32) and Cx36 in Hippocampus and Enhanced Vulnerability of Cx32 Knock-Out Mice
J. Neurosci.,
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J. Szabadics, A. Lorincz, and G. Tamas
{beta}and {gamma} Frequency Synchronization by Dendritic GABAergic Synapses and Gap Junctions in a Network of Cortical Interneurons
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N. Savic, P. Pedarzani, and M. Sciancalepore
Medium Afterhyperpolarization and Firing Pattern Modulation in Interneurons of Stratum Radiatum in the CA3 Hippocampal Region
J Neurophysiol,
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R. D. Traub, R. Bibbig, A. Piechotta, R. Draguhn, and D. Schmitz
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J Neurophysiol,
March 1, 2001;
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B. Teubner, B. Odermatt, M. Guldenagel, G. Sohl, J. Degen, F. F. Bukauskas, J. Kronengold, V. K. Verselis, Y. T. Jung, C. A. Kozak, et al.
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C. T. Dickson, G. Biella, and M. de Curtis
Evidence for Spatial Modules Mediated by Temporal Synchronization of Carbachol-Induced Gamma Rhythm in Medial Entorhinal Cortex
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TOP
ABSTRACT
INTRODUCTION
