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The Journal of Neuroscience, August 1, 2001, 21(15):5824-5831
 and  Frequency Synchronization by Dendritic
GABAergic Synapses and Gap Junctions in a Network of Cortical
Interneurons
János
Szabadics1, 2,
Andrea
Lorincz1, and
Gábor
Tamás1, 2
1 Department of Comparative Physiology, University of
Szeged, Szeged H-6726, Hungary, and 2 Medical Research
Council Anatomical Neuropharmacology Unit, University Department of
Pharmacology, University of Oxford, Oxford, OX1 3TH, United Kingdom
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ABSTRACT |
Distinct interneuron populations innervate perisomatic and
dendritic regions of cortical cells. Perisomatically terminating GABAergic inputs are effective in timing postsynaptic action
potentials, and basket cells synchronize each other via gap junctions
combined with neighboring GABAergic synapses. The function of dendritic GABAergic synapses in cortical rhythmicity, and their interaction with
electrical synapses is not understood.
Using multiple whole-cell recordings in layers 2-3 of rat
somatosensory cortex combined with light and electron microscopic determination of sites of interaction, we studied the interactions between regular spiking nonpyramidal cells (RSNPCs). Random samples of
unlabeled postsynaptic targets showed that RSNPCs placed GABAergic synapses onto dendritic spines (53 ± 12%) and shafts (45 ± 10%) and occasionally somata (2 ± 4%). GABAergic interactions
between RSNPCs were mediated by 4 ± 2 axodendritic synapses and
phased postsynaptic activity at  frequency but were ineffective in
phasing at  rhythm. Electrical interactions of RSNPCs were
transmitted via two to eight gap junctions between dendritic shafts
and/or spines. Elicited at and frequencies, gap junctional
potentials timed postsynaptic spikes with a phase lag, however strong
electrical coupling could synchronize presynaptic and postsynaptic
activity. Combined unitary GABAergic and gap junctional connections of
moderate strength produced and frequency synchronization of the
coupled RSNPCs.
Our results provide evidence that dendritic GABAergic and/or gap
junctional mechanisms effectively transmit suprathreshold information
in a population of interneurons at behaviorally relevant frequencies. A
coherent network of GABAergic cells targeting the dendrites could
provide a pathway for rhythmic activity spatially segregated from
perisomatic mechanisms of synchronization.
Key words:
interneuron; synchronization; dendrite; gap junction; GABA; network
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INTRODUCTION |
Oscillatory activity in different
frequency bands occurs in the EEG during various behavioral states in
mammals, including humans (Niedermeyer and Lopes da Silva, 1993 ).
Particular cortical rhythms are clearly stimulus- and task-specific
(Buzsaki et al., 1983; Singer, 1993; Steriade et al., 1993). band
EEG activity has been observed in the neocortex in vivo
associated with a number of cognitive processes, such as perception or
attentional mechanisms (Steriade et al., 1993, 1996; Lisman and Idiart,
1995; Mainen and Sejnowski, 1995; Singer and Gray, 1995; Buzsaki, 1996;
Jefferys et al., 1996), and rhythms at 20 Hz are related to
voluntarily controlled sensorimotor actions (Salmelin et al., 1995).
Cortical GABAergic mechanisms have been implicated in governing
population activity (Lytton and Sejnowski, 1991; Buzsaki and Chrobak,
1995; Cobb et al., 1995; Traub et al., 1996; Fisahn et al., 1998).
Electrical synapses play a role in neuronal synchrony (Christie et al.,
1989; Draguhn et al., 1998; Mann-Metzer and Yarom, 1999), and gap
junctional coupling can promote synchronous activity in connections of
cortical interneurons (Galarreta and Hestrin, 1999; Gibson et al.,
1999; Koos and Tepper, 1999; Tamás et al., 2000; Venance et al.,
2000). The precise spatiotemporal cooperation of gap junctional
coupling with GABAergic synapses between basket cells further enhances populational coherence (Tamás et al., 2000).
GABAergic cells subdivide the surface of their target neurons (Somogyi
et al., 1998), but most experiments addressing synchronization either
did not examine the location of the inputs or were focused on
perisomatic mechanisms (Cobb et al., 1995; Gupta et al., 2000; Tamás et al., 2000). Recent evidence suggests that a delicate balance of perisomatic and dendritic inhibition is essential in maintaining normal cortical rhythmogenesis because a deficit in dendritic inhibition could reduce seizure threshold, whereas enhanced somatic inhibition would prevent the continuous occurrence of epileptiform activity (Cossart et al., 2001). A particular
subcellular domain of GABAergic and/or electrical communication might
result in compartmental interaction of synaptic and voltage-gated
conductances, resulting in the domain-specific processing of
subthreshold and suprathreshold operations. In this work we identified
a population of neocortical interneurons with dendritic target
preference, which forms a network interacting via gap junctions, and
GABAergic synapses. Neurons of this network are capable of engaging
coherent activity and can be activated by local pyramidal cells at and frequencies.
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MATERIALS AND METHODS |
Electrophysiology. Slices were obtained from Wistar
rats (postnatal day 18-25) and maintained as described
(Tamás et al., 2000). Whole-cell patch clamp recordings were
performed at ~35°C from concomitantly recorded pairs, triplets, or
quadruplets of layer 2-3 putative interneurons and/or pyramidal cells
as detailed previously (Tamás et al., 2000). Micropipettes (5-7
M ) were filled with (in mM) 126 K-gluconate, 4 KCl, 4 ATP-Mg, 0.3 GTP-NA2, 10 HEPES, 10 creatine
phosphate, and 8 biocytin, pH 7.25, 300 mOsm. Signals were filtered at
5 kHz, digitized at 10 kHz, and analyzed with Pulse software (Heka,
Lambrech/Pfalz, Germany). Presynaptic cells were stimulated with brief
(2 msec) suprathreshold pulses at 60 msec intervals (16.6 Hz) for the
paired pulse protocol and at 19 and 37 Hz for the and frequency
phasing paradigm. Depression and facilitation of EPSPs or IPSPs fully
develops only after four or more postsynaptic events, therefore we used
6-10 presynaptic cycles to test the effect of the use-dependent
modification of PSPs on the phasing of postsynaptic activity. We
applied the same paradigm throughout the study for consistency. Trains
were delivered at >5 sec intervals, to minimize intertrial
variability. During subthreshold paradigms, postsynaptic cells were
held at  51 ± 4 mV membrane potential. For phasing trials, they
were depolarized with constant current injections just above threshold
to elicit firing. Unless specified, traces shown are averages of
30-200 episodes. The amplitude of postsynaptic events was defined as the difference between the peak amplitude and the baseline value measured before the PSP onset. Firing probability plots were
constructed from 50-100 consecutive trials as follows: within the
interval separating two presynaptic action potentials, postsynaptic
spike latencies were measured from the peak of the preceding
presynaptic action potential. Subsequently, the data were pooled from
cycles according to the characteristics of the postsynaptic responses (see Results). Controls were collected before the onset of the presynaptic spike train using identical cycle duration, and data obtained during presynaptic activation were normalized to control. Data
are given as mean ± SD. Mann-Whitney U test and
Friedman test were used to compare datasets, and differences were
accepted as significant if p = 0.05. Connections were
classified by cluster analysis based on postsynaptic cell firing
probability (Statistica for Windows; StatSoft, Tulsa, OK).
Joining trees were constructed by Ward's method of amalgamation and
were based on Euclidean distances.
Histology. Visualization of biocytin was performed as
described (Buhl et al., 1994; Tamás et al., 1997).
Three-dimensional light microscopic reconstructions were performed
using Neurolucida (MicroBrightfield, Colchester, VT) with 100×
objective; dendrogram constructions and synaptic distance measurements
were aided by Neuroexplorer (MicroBrightfield) software. Dendrograms
represent only the dendrites involved in the connections. Correlated
light and electron microscopy was performed as described earlier (Buhl et al., 1994; Tamás et al., 1997).
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RESULTS |
Several hundred simultaneous dual, triple, and quadruple
recordings of neurons in layers 2-3 of rat somatosensory cortex
provided 28 RSNPCs to RSNPC connections and 12 pyramidal cell (PC) to
RSNPC connections. RSNPCs were identified based on their physiological and anatomical properties (Cauli et al., 1997; Kawaguchi and Kubota, 1997; Cauli et al., 2000). Similar to RSNPCs identified earlier they
responded to long (800 msec) depolarizing current pulses with a regular
spiking firing pattern showing first to second spike amplitude
reduction of 23 ± 11% and input resistance of 375 ± 117 M (Fig. 1A). Local
pyramidal cells elicited unitary EPSPs in RSNPCs with paired pulse
depression (n = 12; amplitude of the first response,
1.24 ± 1.25 mV; paired pulse ratio, 56 ± 14%) (Porter et
al., 1998). The dendrites of RSNPCs originated from the two poles of
their elongated somata (Figs.
2C,
3B,C, 4C) and were sparsely spiny (Fig.
3E,F). The axons formed a dense cloud around the
dendritic tree and sent a loose bundle of radial branches spanning all
layers of the cortex (Fig. 3B). High-order axonal branches
of RSNPCs ran radially and branched rectangularly (Figs. 2C,
4C). Electron microscopic random samples of unlabeled postsynaptic targets (n = 267) taken from layers 2-5
showed that RSNPCs (n = 10) innervated dendritic spines
(53 ± 12%) and shafts (45 ± 10%) and occasionally somata
(2 ± 4%) (Fig. 1B). Detailed analysis of
serial sections revealed that only 44 ± 21% of postsynaptic targets identified as dendritic spines received asymmetrical
synapses.
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Figure 1.
Identification of RSNPCs and modulation of their
firing by presynaptic and frequency activity of layer 2/3
pyramidal cells. Response of an RSNPC to a depolarizing
(Aa; 180 pA) and hyperpolarizing (Ab;
100 pA) current pulse. Biocytin-filled axon terminals
(t) of RSNPCs formed synapses
(arrows) with unlabeled dendritic
(d) shafts (Ba) and spines
(s) (Bb). Ca,
Pyramidal cell firing at 19 Hz (top) elicited EPSPs
showing marked activity-dependent depression in a postsynaptic RSNPC
(middle). Subsequently, the postsynaptic cell was
tonically depolarized to fire at a frequency of ~4 Hz (bottom,
50 consecutive superimposed sweeps). Cb, Firing
probability plot of the postsynaptic RSNPC during a representative
presynaptic action potential cycle shows that only the first three
cycles were effective in phasing postsynaptic activity at frequency.
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Figure 2.
Dendritic GABAergic synapses can phase somatic
action potential generation in a RSNPC to RSNPC connection. Data
acquired from the presynaptic and postsynaptic cells are presented in
gray and black, respectively.
Aa, Repetitive presynaptic firing at 19 Hz
(top) resulted in the summation of unitary IPSPs
followed by the stabilization of their amplitude in the postsynaptic
cell (middle). When tonically depolarizing to fire, the
postsynaptic RSNPC became effectively entrained with a phase lag of
~41 msec throughout the entire duration of presynaptic activity
(bottom, 50 consecutive sweeps). Ab,
Distribution of postsynaptic firing probability during a representative
presynaptic action potential cycle. Ba, Repeating the
experiment shown in A with 37 Hz presynaptic activation
(top) resulted in early summation and subsequent
stabilization of IPSP amplitude (middle). GABAergic
synapses between RSNPCs were not effective in phasing postsynaptic
firing at frequency as shown by 50 consecutive superimposed sweeps
(Ba, bottom) and average firing probability distribution
during a presynaptic cycle (Bb). C,
Distribution of GABAergic input on the dendritic tree of the
postsynaptic RSNPC (black). The axon of the presynaptic
cell (gray) innervated secondary and tertiary
dendrites (arrows), as detected by light microscopy.
D, Dendrogram representing the innervated dendritic
segments of the postsynaptic cell and three-dimensional distances of
synapses (arrows).
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Figure 3.
Gap junctional connections between RSNPCs.
A-H, Synchronization of a pair of
RSNPCs by strong gap junctional coupling. Aa, Electrical
coupling produces gap junctional potentials of relatively stable
amplitude (middle) in response to presynaptic trains of
action potentials delivered at 37 Hz (top). The
scattergram represents the timing of individual action potentials in 50 consecutive trials during tonic depolarization of the postsynaptic
cell. Robust gap junctional coupling was highly potent in synchronizing
presynaptic and postsynaptic activity, as shown by the overlay of the
50 trials (bottom). Ab, Distribution of
postsynaptic action potentials relative to a presynaptic cycle.
B-H, Anatomical correlates of the electrical
interaction shown in A. B,
Reconstructions of RSNPC 1 (soma and dendrites, gray;
axon, black) and RSNPC 2 (soma and dendrites,
black; axon, gray) cells. Cortical layers
are indicated in the middle
(I-V). C, Relative arrangement of
somata and dendrites of the coupled cells. Electron micro-
(Figure legend continues.) scopically identified gap junctions
(arrowheads) mediating the interaction between the
coupled cells were found on dendrites. D, Dendrograms
representing three-dimensional dendritic distances of gap junctions
(arrowheads). E-H, Examples of the eight
electron microscopically identified gap junctions
(arrowheads) between the RSNPCs. Insets
show the junctional regions at higher magnification. E,
Dendritic spines (s) establish a gap junction
between RSNPC 1 (left) and RSNPC 2 (right; d, parent dendritic shafts).
F, Gap junction between a dendritic spine
(s) of RSNPC 1 and a dendritic shaft
(d) of RSNPC 2. G-H, Dendritic
shafts of RSNPC1 and 2 (d) form gap junctions.
Note the parallel membrane appositions with widened extracellular space
of 21-25 nm (*) adjacent to both dendrodendritic gap junctions.
Synaptic junctions are indicated (arrows) between
unlabeled terminals (t) and the dendrites of
RSNPC 1. Electrical coupling between RSNPCs entrained postsynaptic
firing with a phase lag in most pairs examined. Ia,
Presynaptic action potentials at 37 Hz (top)
elicited gap junctional potentials of moderate amplitude in the
postsynaptic cell (middle, same scale as in
Aa). When tonically depolarizing the postsynaptic RSNPC
to fire, postsynaptic action potentials became entrained with a phase
lag of ~6 msec throughout the entire duration of presynaptic activity
(50 consecutive sweeps). Ib, Distribution of
postsynaptic firing probability during a representative presynaptic
action potential cycle.
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Figure 4.
Synchronization of RSNPCs through combined unitary
gap junctions and GABAergic synapses targeting the dendritic domain.
Data obtained from the presynaptic and postsynaptic cells are presented
in gray and black, respectively.
Aa-Bb, Presynaptic action potentials evoked at 19 and 37 Hz (Aa, Ba, top)
elicited spikelets followed by short-latency IPSPs in the postsynaptic
neuron (middle). Dual coupling of moderate strength
synchronized presynaptic and postsynaptic firing, as shown by 50 consecutive trials during tonic depolarization of the postsynaptic cell
(Aa, Ba, bottom) and the probability plots of
postsynaptic firing during a representative presynaptic cycle
(Ab, Bb). C, The route of presynaptic
dendrites and axons (gray) to gap junctions
(arrowheads) and GABAergic synapses
(arrows) on the postsynaptic cell
(black). The dendrites and axons of the presynaptic cell
are truncated for clarity. D, Dendrograms representing
the dendritic branches of the two RSNPCs involved in the connections
and three-dimensional distances of the sites of interaction. E,
F, Examples of the two electron microscopically identified gap
junctions and the three GABAergic synapses between the RSNPCs.
Insets on the right show the junctional
regions at higher magnification. E, Gap junction
(arrowhead) between dendritic shafts
(d) of the presynaptic (right) and
postsynaptic (left) cell. F, A terminal
(t) of the presynaptic cell establishes a
synaptic junction (arrow) on a dendritic shaft
(d) of the postsynaptic cell.
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Rhythmic activation of RSNPCs by local PCs was tested in six pairs at
and frequencies (19 and 37 Hz, respectively). Presynaptic PC
firing at both frequencies resulted in use-dependent depression of
postsynaptic unitary EPSPs in all RSNPCs (Fig. 1Ca).
Presynaptic spike trains at rhythm increased the mean frequency of
ongoing postsynaptic firing to 125 ± 14% of the control value,
respectively (from 4.2 ± 1.4 to 5.3 ± 1.7 Hz) (Figs.
1Ca, 5B). frequency presynaptic activation entrained postsynaptic firing during
the first three presynaptic cycles. During these cycles, postsynaptic firing probability was significantly higher in the first three bins
(0-22.3 msec) after the preceding presynaptic spike than later (Figs.
1Cb, 5B). In parallel with the depression of
unitary EPSPs, phasing effectiveness of PCs on RSNPC firing faded
during the rest of presynaptic activity (Fig. 1Cb). Similar
results were obtained at frequency PC activation (Fig.
5B). When driving the PCs at 37 Hz, the mean firing rate of
postsynaptic RSNPCs was accelerated to 132 ± 26% of the control,
and entrainment of postsynaptic firing was limited to the first two
(n = 3 pairs) or three (n = 3 pairs)
presynaptic cycles. During these cycles, postsynaptic firing
probability was significantly higher in the second and third bins
(7.4-22.3 msec) after the preceding presynaptic spike than during the
rest of bins (Figs. 1Cb, 5B).
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Figure 5.
Differential entrainment of suprathreshold
activity by inputs targeting RSNPCs. A, Representative
presynaptic cycles at (19 Hz) and (37 Hz) frequency.
B-E, Firing probability plots of postsynaptic RSNPCs
during representative presynaptic action potential cycles shown in
A when EPSPs (B; n = 6), IPSPs (C; n = 5), gap junctions
(D; n = 4), and dual electrical and
GABAergic synapses (E; n = 6)
mediated unitary interactions. In pyramid-to-RSNPC connections, only
the first two presynaptic cycles entrained postsynaptic firing in all
pairs; the rest of the cycles are not shown (Fig. 1Cb).
The two electrical-only connections with the highest coupling ratios
and numbers of gap junctions are not presented in this figure (see
Results and Fig. 3A-H). F,
Cluster analysis of the data presented in B-E.
Controls, connections mediated by IPSPs, and combined electrical and
GABAergic coupling form distinct groups, interactions through gap
junctions only, and EPSP overlap. Dlink/Dmax, Linking
and maximal Euclidean distances.
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We identified GABAergic, electrical, and combined GABAergic and
electrical connections between RSNPCs. In pairs of RSNPCs connected by
chemical synapses only (n = 12), light-microscopic analysis of six fully visualized cell pairs indicated 4 ± 2 close appositions between presynaptic axons and postsynaptic dendrites at a
mean distance of 63 ± 28 µm from the somata (Fig.
2C,D). All GABAergic connections were unidirectional between
RSNPCs in our sample. Measured at 51 ± 3 mV membrane potential,
unitary IPSPs between RSNPCs were 0.54 ± 0.23 mV in amplitude
(n = 12). Bicuculline completely abolished the
responses (20 µM; n = 3). Repetitive presynaptic firing at 19 and 37 Hz resulted in the summation
of postsynaptic unitary IPSPs followed by the stabilization of their
amplitude ~ 198 ± 49 and 238 ± 57% of the amplitude
of averaged single events, respectively (n = 6) (Fig.
2Aa,Ba). Presynaptic spike trains (19 Hz) decreased
the mean frequency of spontaneous postsynaptic firing to 79 ± 18% of the control value (from 4.6 ± 1.9 to 3.6 ± 1.7 Hz).
Postsynaptic firing was entrained for the entire duration of
presynaptic activation. Postsynaptic firing probability was
significantly smaller in the second and third bins (7.4-22.3 msec)
after the preceding presynaptic spike than during the first, sixth, and
seventh bins (0-7.4 and 37.1-52 msec) in a cycle (Figs.
2Ab, 5C). frequency presynaptic
activation (37 Hz) could decrease the mean postsynaptic discharge rate
from 4.7 ± 1.7 to 3.2 ± 1.3 Hz (69 ± 12%) but was
not effective in phasing postsynaptic action potential generation
(Figs. 2B, 5C).
The second class of RSNPC to RSNPC connections was mediated by
electrical synapses (n = 12). Light-microscopic mapping
in five fully recovered pairs detected 3 ± 3 close appositions
(range, 2-8) exclusively between dendrites at a mean distance of
77 ± 34 µm from the somata (Fig. 3B-D). Electron
microscopic analysis of the suspected coupling sites was performed in
one cell pair, leading to the identification of eight gap junctions in
the connection at dendritic distances of 72 ± 16 µm (cell 1)
and 63 ± 36 µm (cell 2) from the somata (Fig.
3C-H). Two gap junctions were established between
dendritic spines, one between a spine and a dendritic shaft, and four
gap junctions linked dendritic shafts. Analysis of serial ultrathin
sections showed in all four dendritic shaft to dendritic shaft cases
that the junctional region was composed of the gap junction and an
immediately adjacent patch of membranes running parallel for 0.3-0.9
µm at a rigid distance of 21-25 nm (Fig. 3G,H).
The latter value is characteristic of desmosomes and/or synaptic
clefts, but the electron opaque reaction end product prevented further
identification of junctional components.
All electrical connections between RSNPCs were reciprocal. Gap
junctional potentials (GJPs) showed a relatively wide range in
amplitude (0.07-2.42 mV; 0.62 ± 0.74 mV) at 50 ± 3 mV
membrane potential and had an average duration of 19.6 ± 8.2 msec, as measured at half amplitude. They followed presynaptic action
potentials with a delay of 0.40 ± 0.26 msec, measured as the
period spanning the maximal rates of rise of the presynaptic action
potential and the GJP, respectively. The average amplitude ratio
(coupling coefficient) for GJPs and presynaptic potentials was
0.66 ± 0.83% (range, 0.04-2.58%) and 4.6 ± 3.1% (range,
2.4-10.6%) when eliciting action potentials and applying long current
steps (200 pA, 300 msec duration) in the first neuron to elicit a
response in the second neuron. Coupling strength was similar in both
directions and did not show voltage dependence between 80 and 40 mV
postsynaptic membrane potential (n = 4). Both
amplitudes and kinetics of GJPs remained unchanged during repetitive
presynaptic firing (Fig. 3Aa,Ia). The effect on
unitary GJPs on postsynaptic suprathreshold activity was investigated
at 19 and 37 Hz in six connections. For a given pair, timing of
postsynaptic firing was similar at both frequencies tested, and members
of a pair phased one another with similar efficacy regardless of the
direction. In four of six pairs, 19 Hz presynaptic activation
accelerated the mean firing rate of postsynaptic RSNPCs to 120 ± 10% of the control. Postsynaptic firing probability was significantly
higher in the first two bins (0-14.9 msec) after the preceding
presynaptic spike than during the last three bins (29.7-52 msec) of a
cycle (Fig. 5D). GJPs arriving at frequency increased
ongoing postsynaptic firing, and firing probability was significantly
higher in the second bin (3.9-7.7 msec after the presynaptic spike)
than in the rest of bins in a cycle (Figs. 3I,
5D). In the two pairs with the highest coupling ratios and
numbers of gap junctions, GJPs synchronized presynaptic and
postsynaptic firing at and frequencies with no apparent phase
lag (bin width, 3.9 msec) and a relatively narrow temporal scatter of
action potentials (Fig. 3A).
Six RSNPC to RSNPC connections were mediated by combined GJPs and
IPSPs. The GABAergic component of all dual electrical and chemical
connections was unidirectional. Light microscopic mapping of three
fully recovered pairs revealed that gap junctions as well as chemical
synapses were located in the dendritic domain of the postsynaptic cells
at a mean distance of 59 ± 21 and 75 ± 18 µm from the
somata, respectively. Detailed electron microscopic analysis of one
pair confirmed such arrangement of connections and identified two gap
junctions between dendritic shafts (one of them showing rigid widening
of extracellular space adjacent to the gap junction) and three
GABAergic synapses on dendrites (Fig. 4C-F).
Postsynaptic responses were composed of GJPs followed by short-latency
IPSPs of stable amplitude (Fig. 4A,B). Presynaptic spike trains at 19 and 37 Hz decreased the mean frequency of ongoing postsynaptic firing to 91 ± 11% and 84 ± 8% of control
values, respectively (from 5.08 ± 1.19 to 4.62 ± 1.13 Hz
and from 5.22 ± 1.34 to 4.38 ± 1.27 Hz). After the onset of
presynaptic spike trains, postsynaptic firing was instantly
synchronized at and frequencies, with maximal postsynaptic
action potential probability in the first bin (bin widths, 7.4 and 3.9 msec) (Figs. 4Ab,Bb, 5E). Firing occurred
synchronously in the coupled cells during the entire length of
presynaptic activation.
Cluster analysis of postsynaptic firing probability in response to and frequency presynaptic firing resulted in the clear delineation
of controls, connections mediated by IPSPs, and combined electrical and
GABAergic coupling (Fig. 5F). Interactions via moderate gap junctional coupling and EPSPs clustered together (Fig.
5F), but the two electrical connections mediated by
powerful coupling formed a separate group at both frequencies (data not shown).
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DISCUSSION |
We have identified a novel interneuronal network in the cortex
interconnected by electrical and GABAergic synapses. RSNPCs form
dendritic gap junctions with other RSNPCs and establish GABAergic synapses on the dendritic domain of postsynaptic cells. Electrical, GABAergic, or combined GABAergic and gap junctional signals targeted to
the dendrites are capable of timing somatic action potential generation
in the network of RSNPCs at behaviorally relevant frequencies.
Interneurons forming the network identified here are distinct of
GABAergic cell classes known to form electrically coupled networks in
the cortex (Galarreta and Hestrin, 1999; Gibson et al., 1999;
Tamás et al., 2000; Venance et al., 2000). The regular spiking
firing pattern in combination with depressor unitary EPSPs demarcate
RSNPCs both from fast-spiking cells and from low-threshold spiking and
bitufted cells (Reyes et al., 1998; Gibson et al., 1999), and these
electrophysiological parameters are similar to those of vasoactive
intestinal polypeptide-immunoreactive interneurons (Kawaguchi and
Kubota, 1996; Cauli et al., 2000). In agreement with earlier results
(Kawaguchi and Kubota, 1997; Tamás et al., 1997), we have found
that RSNPCs place symmetrical synapses onto dendritic spines and
shafts. These results would identify RSNPCs as double bouquet cells
(Somogyi and Cowey, 1981; Tamás et al., 1997), but the finding
that only less than half of postsynaptic targets identified as
dendritic spines received asymmetrical synapses questions the origin of
postsynaptic dendritic appendages. Although the synaptology of
interneuronal spines are not known, the spines receiving excitatory
synapses are most likely originate from pyramidal dendrites; the ones
receiving GABAergic innervation only could belong to pyramidal cells as
well as GABAergic interneurons. Double bouquet cells target other
GABAergic neurons (Tamás et al., 1998), there are known types of
interneuron preferentially innervating other GABAergic cells in the rat
(Gulyas et al., 1996; Meskenaite, 1997), and the distinction between
these classes is not yet clear. Gap junctions between RSNPCs also
connect dendritic shafts and spines and, moreover, GABAergic synapses
and gap junctions are placed at similar distances from the soma of
RSNPCS. Therefore, similarly to the network of cortical basket cells
(Tamás et al., 2000), chemical and electrical synapses target the
same subcellular domain of RSNPCs equalizing the time required for
postsynaptic signal propagation. Accurate spatial integration could be
further promoted by juxtaposition of gap junctions, dendrodendritic
synapses, and/or desmosomes found between smooth dendritic shafts in
the primate motor cortex (Sloper and Powell, 1978) and between
parvalbumin-immunoreactive dendrites in the hippocampus (Fukuda and
Kosaka, 2000). We found a rigid widening of the extracellular space
next to the gap junctions in six of five contacts between dendritic
shafts of RSNPCs, but our method for the visualization of functionally
coupled cells did not allow the differentiation of desmosomes and
dendrodendritic synaptic junctions.
We provide evidence that dendritically targeted GABAergic synapses are
effective in timing somatic action potentials in the postsynaptic
RSNPCs. Mechanisms underlying such phasing are not yet known. GABAergic
cell types elicit IPSCs and IPSPs with remarkably different kinetics
(Gupta et al., 2000), which could reflect distinct postsynaptic
receptor properties (Draguhn et al., 1990; Mody et al., 1994). Currents
activated by hyperpolarization (Ih)
are present in RSNPCs, but not as prominent as in pyramidal cells and
bitufted cells (our unpublished data; Cauli et al., 2000). Therefore,
activation and/or deinactivation of other voltage-gated cation
conductances and/or by passive dendritic properties could be the major
factors in shaping the relatively fast decay of IPSPs. Dendritic
GABAergic synapses between RSNPCs are able to phase postsynaptic cells
in the frequency band, which is clearly faster than the theta
frequency range of rebound activation detected in connections mediated
by perisomatically placed GABAergic synapses on pyramidal cells (Cobb et al., 1995) as well as on interneurons (Tamás et al., 2000). The rebound activation might be even faster in vivo, when
the input resistance of the cells is likely to be lower because of ongoing background synaptic activity. This could improve phasing between RSNPCs in the frequency band. Theta and / rhythms are
linked to distinct behaviors (Buzsaki et al., 1983; Singer, 1993;
Steriade et al., 1993), and our results suggest that diverse populations of GABAergic cells might be differentially involved in
cortical network operations during a particular activity.
Unitary EPSPs could initiate firing in RSNPCs with latencies slightly
longer to what has been found in hippocampal interneurons (Fricker and
Miles, 2000). These authors measured the timing of spikes elicited from
just subthreshold membrane potentials, but we have tested the
effectiveness of GJPs and EPSPs (and IPSPs and dual coupling) on
spontaneous ongoing firing. The set of voltage-gated conductances
active at subthreshold membrane potentials and during spontaneous
repetitive firing is likely to be different and might explain the
discrepancy. The amplitude of GJPs versus EPSPs might also influence
the immediacy of spikes after the onset of the postsynaptic potentials
by activating different amounts and or populations of voltage-gated
channels. In addition to spike triggering, suprathreshold activity of
RSNPCs can be rhythmically timed with a phase lag by neighboring
pyramidal cells in the and frequency range.
Strong bidirectional electrical coupling could produce synchronization
of RSNPCs, but on average, combined chemical and electrical unitary
connections were most effective in synchronizing presynaptic and
postsynaptic firing. In our sample, all GABAergic connections were
unidirectional between RSNPCs including the GABAergic component of dual
electrical and chemical connections. The implications of unidirectional
GABAergic coupling in combination with reciprocal gap junctional
connections are not clear. RSNPCs are embedded into a network
interconnected by chemical, electrical, and dual unitary connections,
and a particular postsynaptic cell is likely to receive convergent GJPs
and IPSPs from some RSNPCs that might be precisely synchronized by dual
coupling. This scenario suggests that dual connections would rule the
operation of RSNPCs at the network level. Preferred rhythms of RSNPC
population oscillations might be in the and probably frequency
band set by the timing of rebound activation after unitary IPSPs within
the network. Coherent output of RSNPCs could provide a powerful
dendritic pathway of rhythmic information processing spatially and
temporally segregated from perisomatic mechanisms of synchronization.
The cooperation of GABAergic synapses and gap junctions appears to be
limited to a single population of interneurons (Galarreta and Hestrin, 1999; Gibson et al., 1999; Tamás et al., 2000; Venance et al., 2000), therefore synchronization might be more prominent within populations than across different interneuron types. This might explain
the effectiveness of soma and dendrite targeting interneurons in timing
postsynaptic activity of pyramidal cells though a precisely synchronized, robust, but perisomatically and dendritically channeled GABAergic flow of information.
| |
FOOTNOTES |
Received Feb. 8, 2001; revised May 8, 2001; accepted May 18, 2001.
This work was supported by the James S. McDonnell Foundation (Eastern
European Science Initiative Grant 97-39), the Wellcome Trust,
and the Hungarian Scientific Research Fund (D32815). G.T. was a
János Bolyai Research Scholar during part of this project. We thank Prof. P. Somogyi for his comments on an earlier version of
this manuscript.
J.S. and A.L. have contributed equally to this work.
Correspondence should be addressed to Dr. Gábor Tamás,
University of Szeged, Department of Comparative Physiology,
Középfasor 52, Szeged, H-6726, Hungary. E-mail:
gtamas{at}sol.cc.u-szeged.hu.
| |
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TOP
ABSTRACT
INTRODUCTION
