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The Journal of Neuroscience, August 1, 1998, 18(15):5640-5651
Functionally Distinct Groups of Interneurons Identified During
Rhythmic Carbachol Oscillations in Hippocampus In Vitro
Lori L.
McMahon,
John H.
Williams, and
Julie A.
Kauer
Department of Neurobiology, Duke University Medical Center, Durham,
North Carolina 27710
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ABSTRACT |
During distinct behavioral states, the hippocampus exhibits
characteristic rhythmic electrical activity. Evidence in
vivo suggests that both principal pyramidal cells and GABAergic
interneurons participate in generating oscillations. We found that
during rhythmic oscillations in area CA3, functionally distinct classes
of interneurons could be identified, although all recorded interneurons
had similar dendritic and axonal arbors. One group of interneurons was
powerfully excited by CA3 pyramidal cells, whereas two other
interneuron groups were relatively unaffected by pyramidal cell firing.
One of these groups of interneurons was potently inhibited by other local interneurons during the pyramidal cell bursts. Our findings emphasize that morphologically similar cells are wired together very
differently within the local circuit. The classes of hippocampal interneurons we have tentatively defined may be used during distinct behavioral states to switch the local network from one oscillatory state to another.
Key words:
hippocampus; carbachol; oscillations; interneurons; GABAergic; epileptiform
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INTRODUCTION |
The hippocampus exhibits
characteristic oscillations in vivo correlated with specific
behavioral states (Buzsaki et al., 1983 ; Bland, 1990; Buzsaki and
Chrobak, 1995) and is also susceptible to rhythmic firing during
temporal lobe epileptic seizures (Traub and Miles, 1991; Mody and
Staley, 1994; Traub and Jefferys, 1994; Traub et al., 1996a).
Although inhibitory interneurons constitute a small percentage of the
neurons in hippocampus, their extensive axon arbors form GABAergic
synapses on hundreds of local pyramidal cells (Buhl et al., 1994; Miles
et al., 1996) (for review, see Freund and Buzsaki, 1996). As a
consequence, interneurons influence the excitability of large groups of
pyramidal cells and can therefore synchronize their electrical activity
(Cobb et al., 1995; Whittington et al., 1995; Traub et al., 1996b; Toth
et al., 1997). Control of interneuron excitability provides a
direct route through which the output of the entire hippocampus can be
altered. Therefore, understanding the control of interneuron
excitability is fundamental to understanding patterns of electrical
activity in the hippocampus.
Hippocampal interneurons are excited by numerous neurotransmitters
including glutamate, serotonin, acetylcholine, and norepinephrine (Lacaille and Schwartzkroin, 1988; Sah et al., 1990; McBain and Dingledine, 1993; Bergles et al., 1996; Freund and Buzsaki, 1996; Jones
and Yakel, 1997; McMahon and Kauer, 1997a; McQuiston and Madison, 1997;
Frazier et al., 1998). In slices, electrical stimulation of the
neuropil reveals synaptic responses in interneurons (Lacaille and
Schwartzkroin, 1988; Sah et al., 1990; Maccaferri and McBain, 1995;
McMahon and Kauer, 1997b). However, the levels of spontaneous synaptic
activity normally present in vivo are significantly reduced in vitro, and electrical activation of a heterogeneous
population of afferents by a stimulating electrode does not mimic
natural activation of the local circuit. In light of these
difficulties, we examined the activity of interneurons in
vitro during rhythmic activity generated intrinsically by local
pyramidal cells.
The cholinergic agonist carbachol triggers synchronous rhythmic
oscillations of the membrane potential in pyramidal neurons in the CA3
and CA1 regions (Konopacki et al., 1987; MacVicar and Tse, 1989; Traub
et al., 1992; Huerta and Lisman, 1993, 1995, 1996; Williams and Kauer,
1997). We have recorded directly from interneurons in area CA3 during
these carbachol oscillations. Several studies have suggested that
classes of interneurons may be activated by distinct sets of afferents
and are therefore likely to participate differently during activity in
the local circuit (Sloviter and Nilaver, 1987; Freund and Antal, 1988;
Freund et al., 1990). In support of this idea, we found interneurons
with similar morphological features but distinct patterns of synaptic activity during carbachol oscillations.
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MATERIALS AND METHODS |
Recordings and analysis
Hippocampal slice preparation. All experiments were
performed in strict accordance with a protocol approved by the Duke
University Medical Center Institutional Animal Care and Use Committee.
Slices were prepared from male Sprague Dawley rats aged 17-23 d as
previously described (McMahon and Kauer, 1997a). Using a vibratome,
coronal slices (400 µm) were cut from the middle third of the
hippocampus into ice-cold artificial CSF (in mM:
NaCl, 119; NaHCO3, 26; KCl, 2.5;
NaH2PO4, 1.0; CaCl2,
2.5; MgCl2, 1.3; and D-glucose, 11) saturated with 95% O2 and 5% CO2. Slices were
held after cutting for 1-5 hr in an interface chamber at room
temperature and then transferred to a recording chamber in which the
slice was held submerged between two nets. The bath temperature was
maintained between 29-31°C.
Extracellular recording. Field potentials were recorded from
area CA3b because we previously determined that carbachol oscillations are largest in this area (Williams and Kauer, 1997). Glass
microelectrodes filled with 2 M NaCl were used to record in
stratum radiatum as previously described (Williams and Kauer, 1997).
Field potentials were recorded using an Axoclamp 2A amplifier and
filtered at 25-30 Hz for on-line display and were also collected on
video tape. Data shown for extracellular oscillations are AC-coupled
for clarity.
Interneuron recordings. Tight-seal whole-cell recordings
were obtained from interneurons with cell bodies located in stratum (st.) radiatum or st. oriens of area CA3 or from CA3 pyramidal cells, using techniques described previously (McMahon and Kauer, 1997b). All interneurons and pyramidal cells had cell bodies outside the hilar region (or CA3c) defined by an imaginary line drawn between
the two blades of the dentate granule cells; many of the interneuron
cell bodies were in the region of CA3 closest to the hilus, CA3b in the
classification of Lorente de No (1934). Patch electrodes had
resistances of 2-5 M when filled with (in mM): potassium gluconate, 100; EGTA, 0.6; Na-GTP, 0.3; Na-ATP, 2;
MgCl2, 5; HEPES, 40; and biocytin, 0.4%. Recordings
were made using an Axoclamp 2A amplifier, and cells were recorded at
their resting potential in bridge mode except as noted. Only
interneurons that had overshooting action potentials were accepted for
study. Input resistance ranged from 200 to 700 M, and series
resistance ranged from 10 to 30 M. Input resistance and series
resistance were carefully monitored on-line, and experiments were
discarded if changes >10% were seen. Under our recording conditions,
GABAA receptor-mediated IPSPs reversed polarity at
approximately  60 mV. Records were filtered at 1-2 kHz and recorded
on chart paper and video tape.
Carbachol-induced oscillations. Interneuron recordings
were used only if bath-applied carbachol (Sigma, St. Louis, MO; 50 µM) elicited regular oscillations, defined as >five
consecutive regularly spaced trains of burst activity in the
extracellular field potential records (Williams and Kauer, 1997).
Picrotoxin (Sigma; 100 µM) was bath-applied in some
experiments.
Biocytin processing. Slices were fixed immediately after use
in 4% paraformaldehyde and resectioned at 75 µm. The sections were
reacted as described with avidin-horseradish peroxidase (McBain et
al., 1994), cleared in xylene, and coverslipped. Camera lucida reconstructions were made using a 40× oil immersion objective.
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RESULTS |
Carbachol-induced oscillations in CA3 pyramidal cells
Bath application of carbachol (50 µM) to hippocampal
slices elicited repetitive bursts of rhythmic activity ("carbachol
oscillations") recorded both extracellularly and intracellularly from
CA3 pyramidal neurons (Fig. 1).
Initially, carbachol induced a 5-30 mV depolarization of individual
CA3 pyramidal neurons beyond spike threshold (mean depolarization ± SEM, 15 ± 3 mV; resting membrane potential (RMP), 61 ± 1 mV; n = 10), so that the cells fired
action potentials at high frequency. Within minutes of the initial
depolarization, activity in groups of pyramidal cells became
synchronous, producing bursts of field potentials apparent in
extracellular recordings (Fig. 1A, bottom
trace). Once the population of pyramidal cells was firing in
concert, carbachol oscillations occurred at regular intervals (Fig.
1B). Low-amplitude signals were occasionally observed in the extracellular record leading up to a burst; we speculate that
these are caused by firing in small groups of pyramidal cells before
the population is entirely recruited.
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Figure 1.
Carbachol induces depolarization and synchronous
oscillations in CA3 pyramidal cells. A, Simultaneous
whole-cell current-clamp recording from a CA3 pyramidal cell
(top trace, intracellular) and extracellular dendritic
field potential recording in stratum radiatum of CA3 (bottom
trace, extracellular). Bath perfusion of 50 µM
carbachol (arrow) induces an abrupt 25 mV depolarization
of the pyramidal cell from its resting membrane potential (60 mV)
beyond spike threshold. After 2-3 min in the continued presence of
carbachol, an increase in noise is evident in the extracellular
recording, as multiple pyramidal cells become synchronously active.
B, Within minutes of carbachol application, groups of
pyramidal cells become "entrained" to fire together in a rhythmic
oscillatory pattern observable in both the cell (I,
top) and the population (E,
bottom). Traces on the
right show a single burst on an expanded time scale.
Calibration: A, B, left,
25 mV intracellular, 0.2 mV extracellular, 20 sec; B,
right, 800 msec.
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Together with previous work (MacVicar and Tse, 1989; Traub et al.,
1992; Williams and Kauer, 1997), these results suggest that carbachol
depolarizes CA3 pyramidal cells directly, and excitatory synaptic
connections among these cells then allow the population to fire in a
gradually more and more coordinated manner, eventually producing
regular bursts.
Carbachol-induced oscillations in GABAergic interneurons
We simultaneously recorded from visually identified interneurons
in either stratum radiatum or stratum oriens of area CA3 and
extracellularly from CA3 pyramidal cell dendrites in the same stratum.
We distinguished three interneuron classes based on differing physiological responses during carbachol oscillations in pyramidal neurons. One interneuron class was depolarized to threshold during the
bursts, and several of these cells exhibited a characteristic "run-up" of activity preceding the pyramidal cell burst. A second, rarely encountered interneuron class was hyperpolarized during each
population burst; the hyperpolarization was bicuculline-sensitive, suggesting a powerful GABAergic input to these interneurons. A third
cell class was remarkably unaffected by the bursting activity in nearby
pyramidal cells, indicating that this cell type was not synaptically
driven by CA3 pyramidal cells or local GABAergic interneurons active
during the oscillations.
Class I: st. radiatum interneurons that are depolarized during the
carbachol oscillations
Twenty-seven of 42 CA3 st. radiatum interneurons were excited
during carbachol-induced bursts in pyramidal cells (class I). As
carbachol entered the bath and before the onset of pyramidal cell
bursting, interneurons in this class depolarized by 2-30 mV (10 ± 1 mV; n = 24) from the resting membrane potential
(55 ± 1 mV; n = 23) to threshold and fired action
potentials at high frequency (Fig.
2A; n = 19 of 27; 8 of 27 depolarized but did not reach threshold). The initial
depolarization of the interneuron membrane also occurred in the same
cells after synaptic transmission was blocked by 1 µM
tetrodotoxin (TTX), indicating a direct action of carbachol at
postsynaptic cholinergic receptors (data not shown) (depolarization in
TTX, 100% of that without TTX, n = 3; 50% of that
without TTX, n = 1). These data indicate that class I
cells express cholinergic receptors that strongly depolarize the
interneuron directly. In TTX, carbachol did not induce oscillatory
activity, emphasizing that carbachol oscillations are synaptically
driven.
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Figure 2.
Class I interneurons are depolarized during
oscillations in pyramidal cells. A1, Simultaneous
whole-cell current-clamp recording of a visually identified interneuron
in stratum radiatum of CA3 (I) and
extracellular pyramidal cell dendritic field potential recording in
stratum radiatum (P). Bath perfusion of 50 µM carbachol (arrow) induces an 8 mV
depolarization of the interneuron from the resting membrane potential
(59 mV) to action potential threshold. Within 3-4 min in the
continued presence of carbachol, oscillatory events begin to emerge in
the pyramidal cells (bottom trace). B1,
Synchronous rhythmic bursts appear in the interneuron and pyramidal
cells (6 min in carbachol). In the interim between oscillatory events,
the interneuron returns to the resting membrane potential.
B2, Expanded time scale of a single burst
(bracket) reveals that each event in the pyramidal cell
population is precisely correlated with a burst of two or three action
potentials in the interneuron. C1, C2,
When the cell is hyperpolarized to 70 mV with constant current
injection, some of the population events are now paralleled by
subthreshold EPSPs recorded from the interneuron. Calibration:
A1, B1, C1, 40 mV
intracellular, 0.1 mV extracellular, 20 sec; B2,
C2, 800 msec.
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Once the bursting period began in pyramidal cells, class I interneurons
were excited synchronously with the pyramidal cells, often with bursts
of three to five spikes riding on an EPSP. The membrane potential often
remained depolarized in the continued presence of carbachol. Action
potentials were reduced in amplitude compared with those before
carbachol and often did not overshoot 0 mV (cf. Bianchi and Wong, 1994;
Lukatch and MacIver, 1997); this is probably a result of the documented
blockade of Na+ channels after treatment with
carbachol (Cantrell et al., 1996). At the end of each pyramidal cell
burst, the interneuron hyperpolarized, entering a quiet period before
spiking resumed. Hyperpolarization to 70 mV revealed underlying
subthreshold EPSPs (Fig. 2, compare B,C). In the period between
pyramidal cell bursts, most class I interneurons (14 of 27) fired
single action potentials followed by modest afterhyperpolarizations
(data not shown).
In a subset of interneurons in this class (n = 7 of
27), the membrane potential exhibited a "ramp" depolarization
preceding the oscillation in the pyramidal cell population (Fig.
3). Bursts of action potentials occurred
at high frequency (>30 Hz), increasing as the cells became more
depolarized, and the cells continued firing throughout the field
oscillation. Each action potential during the ramp depolarization was
followed by a prominent afterhyperpolarization. In five of seven
interneurons exhibiting the ramp depolarization, the interneurons fired
bursts of action potentials riding on characteristically broad waves of
depolarization that may be EPSPs or plateau potentials (Fig.
3B2).
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Figure 3.
A subset of class I interneurons exhibit a
characteristic ramp depolarization before the pyramidal cell burst.
A1, Simultaneous whole-cell recording from a stratum
radiatum interneuron (I) and extracellular
pyramidal cell dendritic field potential recording
(P). Carbachol (50 µM) perfusion
(arrow) elicits a 25 mV depolarization of the
interneuron from rest (56 mV). A2, Expanded time scale
(A1, bracketed region) showing that
during the initial bursts of action potentials in the interneuron, the
pyramidal cell population is inhibited. Note the decrease in noise in
the extracellular pyramidal cell recording during interneuron activity
(arrows). B1, left panel,
After 6 min in the continued presence of carbachol, firing in the
interneuron is now entirely correlated with the pyramidal cell bursts.
B2, left panel, Single burst on an
expanded time scale shows that action potentials in the interneuron
increase in frequency just before the pyramidal cell burst.
B1, right panel, When the interneuron is
hyperpolarized to 70 mV with constant current injection, the ramp
depolarization is reduced in amplitude. B2, right
panel, Ramp depolarization is absent when the interneuron is
held at 70 mV (note expanded time scale). Calibration:
A1, B1, 50 mV intracellular, 0.1 mV
extracellular, 10 sec; A2, 800 msec; B2,
400 msec.
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Early during carbachol exposure, each depolarizing burst in the
interneuron did not have a corresponding oscillation in the population
(Fig. 3A). During early uncorrelated bursts of action potentials in one interneuron, inhibition of the pyramidal cells was
clearly observed, as indicated by the decreased noise in the extracellular record (Fig. 3A2, arrows). The
silencing of the pyramidal cell population is presumably attributable
to GABAergic inhibition of multiple local pyramidal cells during firing
in the recorded interneuron. At the onset of carbachol oscillations, these independent oscillatory events in the interneuron may help to
synchronize the firing of local pyramidal cells. Once the population of
pyramidal cells established regular rhythmic oscillations, each burst
in the interneuron became tightly correlated with a population
oscillation in the pyramidal cells (Fig. 3B). When the
interneuron was hyperpolarized to 70 mV, the ramp depolarization was
absent, and multiple excitatory synaptic events were apparent (Fig.
3B, right panels).
Class I interneurons are robustly excited during the firing of CA3
pyramidal cells. Although class I interneurons exhibit both
electrically evoked and spontaneous IPSPs before and during carbachol
treatment (data not shown), during carbachol oscillations these
interneurons are not prevented from firing by other inhibitory interneurons. Class I interneurons also contribute potent inhibition to
groups of pyramidal cells, most clearly seen when the pyramidal cells
have not begun to fire regularly (Fig. 3A2).
Class II: interneurons that are hyperpolarized during the
carbachol oscillations
Interneurons in this class were rarely encountered
(n = 3 of 42) but exhibit such distinct electrical
activity during carbachol oscillations that we have categorized them
into a single class for convenience. Carbachol application elicited a
modest membrane depolarization (0-5 mV) before the onset of bursting
(data not shown). During the burst period in pyramidal cells, class II
interneurons received IPSPs that increased in size when the cell was
held at a depolarized potential (Fig. 4).
When class II interneurons were held hyperpolarized, the IPSPs reversed
polarity at the Cl equilibrium potential,
suggesting that they are GABAA receptor-mediated (Fig.
4A, right panels).
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Figure 4.
Class II interneurons are hyperpolarized during
pyramidal cell bursts. A, left traces,
Class II interneuron held at 35 mV hyperpolarizes during each
pyramidal cell burst. A1, Bottom traces
show a pyramidal cell burst (bracket) with interneuron
IPSPs paralleled by each field event in the extracellular pyramidal
cell recording. A, right traces, When the
cell is held at 70 mV, the burst-associated hyperpolarization in the
interneuron is absent. A2, Expanded time scale of a
burst (A1, bracketed region) shows that
the IPSPs have reversed polarity. B, left
traces, In the same experiment, addition of picrotoxin (100 µM) to the perfusate blocks the burst-associated
interneuron hyperpolarization observed at 35 mV. B2,
left, Expanded time scale unmasks EPSPs, which are
temporally correlated with individual field events. B,
right traces, When the interneuron is held at 70 mV in
the continued presence of picrotoxin, some EPSPs now reach threshold
during the pyramidal cell burst. B2, Traces are
displayed on an expanded time scale. Calibration: A1,
B1, 16 mV intracellular, 0.1 mV extracellular, 12.5 sec;
A2, B2, 500 msec.
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The GABAA receptor antagonist picrotoxin (100 µM) attenuated the hyperpolarization and IPSPs during the
carbachol oscillation (n = 2). In the presence of
picrotoxin, EPSPs were unmasked that were correlated with the field
events during the oscillation (Fig. 4B, left
panels). When the interneuron was hyperpolarized in the presence of picrotoxin, EPSPs during the burst were increased in
amplitude (Fig. 4B, right panels).
We hypothesize that interneurons in this class, although receiving weak
excitatory innervation from local pyramidal cells, also receive potent
inhibitory innervation, perhaps from some of the class I interneurons
that are excited and release GABA during the pyramidal cell
oscillation.
Class III: interneurons whose activity is not correlated with the
oscillation in pyramidal cells
Eleven of 42 interneurons responded differently during carbachol
oscillations than interneurons in either class I or II: these interneurons appeared to be synaptically isolated from the pyramidal cells and are thus referred to as class III. Carbachol depolarized 5 of
11 interneurons in this class to threshold, triggering action potentials at frequencies from 3 to 15 Hz (Fig.
5A). These interneurons continued to fire action potentials at the same frequency during burst
activity in pyramidal cells, without altering their activity (Fig.
5A, right panel, B). When the
membrane potential was hyperpolarized below action potential threshold
(n = 4), small EPSPs were just visible above baseline
noise in two of these interneurons during the pyramidal cell burst; the
other two interneurons were silent during the burst (data not shown).
The remaining class III interneurons (6 of 11) did not reach spike
threshold in carbachol. Three interneurons were silent during the
oscillation in pyramidal cells, and three had EPSPs just visible above
the basal synaptic noise. Taken together, these data suggest that
neither local pyramidal cells nor local interneurons significantly
influence the excitability of class III interneurons during carbachol
oscillations.
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Figure 5.
Class III interneurons have electrical activity
uncorrelated with the pyramidal cell bursts. A,
left traces, Bath application of 50 µM
carbachol (left panel, arrow) elicits a
10 mV depolarization (RMP, 56 mV) in which the cell fires action
potentials at ~8-10 Hz (I).
A, right traces, As the oscillatory
activity begins in the extracellular pyramidal cell recording
(P), the interneuron firing pattern remains
unchanged (6-8 min in carbachol). B, On an expanded
time scale (A, bracketed region) the
interneuron activity is unaffected by the burst in the pyramidal cells.
Calibration: A, 20 mV intracellular, 0.1 mV
extracellular, 10 sec; B, 400 msec.
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Sparse synaptic input to class III interneurons could be an artifact of
slicing. Although it is not possible to rule this out entirely, it is
unlikely for several reasons. The interneuron dendrites observed in
biocytin-filled cells were not shorter or closer to the sliced surface
than for interneurons of the other classes, suggesting we have not
simply removed the synaptic surface. Moreover, electrical stimulation
delivered in st. radiatum always elicited both EPSPs and
picrotoxin-sensitive IPSPs in class III neurons (data not shown), and
carbachol elicited an increase in spontaneous EPSPs and IPSPs in these
cells not correlated with burst activity. Thus, it is very unlikely
that interneurons with normal length dendrites and functional
excitatory and inhibitory synapses would be frequently encountered and
yet entirely disconnected from other local neurons. Thus, these
interneurons receive afferent inputs and are innervated by neurons
excited by carbachol but are not innervated by excitatory and
inhibitory neurons active during carbachol oscillations. We describe
below that the majority of class III interneurons were found in one
particular region of area CA3 (the CA2 region), whereas the majority of
class I interneurons were found elsewhere. This may help to explain the physiological differences observed.
St. oriens interneurons
Nearly all of the interneurons from which we recorded with cell
bodies in st. radiatum had axons primarily localized within st.
radiatum (detailed in the next section). We also wanted to record
responses from interneurons innervating st. pyramidale, so we recorded
from an additional five interneurons with cell bodies in st. oriens,
many of which innervate the pyramidal cell bodies (Freund and Buzsaki,
1996; Miles et al., 1996). Interneurons in st. oriens behaved much like
class I interneurons in st. radiatum. Four of five neurons depolarized
to action potential threshold in response to carbachol with EPSPs
occurring in synchrony with pyramidal cell bursts (Fig.
6A,B).
Therefore, we have considered these interneurons to fall within class
I. In a recording from one st. oriens cell (data not shown) when the
interneuron was firing, the pyramidal cell record grew noticeably
quieter (as in Fig. 3A2 for a st. radiatum interneuron).
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Figure 6.
Oscillatory activity of CA3 stratum oriens
interneurons is similar to class I stratum radiatum interneurons.
A, Stratum oriens interneuron is depolarized (~10 mV;
RMP, 66 mV) during bath application of 50 µM carbachol
(I). Bottom trace
(P) is the extracellular recording from pyramidal
cell dendrites. B1, Pyramidal cell bursts are correlated
with EPSPs in the interneuron. B2, This is most clearly
seen when a burst (A, bracketed region)
is displayed at an expanded time scale. Calibration: A,
B1, 25 mV intracellular, 0.2 mV extracellular, 20 sec;
B2, 800 msec.
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Out-of-phase interneuron
Only 1 of 47 CA3 interneurons displayed rhythmic activity that was
entirely out of phase with pyramidal cell oscillations. This
interneuron was heavily innervated by other GABAergic neurons, as
indicated by an unusually high frequency of spontaneous IPSPs compared
with the other interneurons recorded in this study. Carbachol depolarized the neuron ~4 mV to threshold and, after several minutes in the continued presence of carbachol, the cell exhibited rhythmic depolarizations accompanied by broad action potentials. During the
discharges in the interneuron, the field recording was silent. When the
interneuron repolarized, increased noise was again observed in the
population. The morphological features of this interneuron were not
significantly different from other recorded interneurons (Fig.
7, bottom).
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Figure 7.
Camera lucida reconstructions of biocytin-filled
interneurons. Top left, Example of a class I interneuron
with electrical responses like those shown in Figure 2. Top
right, Example of a class I interneuron that displays the ramp
depolarization before each carbachol-induced oscillation (as
illustrated in Fig. 3). Middle left, Camera lucida
reconstruction of a biocytin-filled class II interneuron (like that in
Fig. 4). Middle right, Camera lucida reconstruction of a
neuron with cell body in st. oriens, with extensive axon ramification
within st. pyramidale, where it is likely to inhibit pyramidal cell
somata (like that in Fig. 6). Scale bars, 100 µm. Bottom
left, Camera lucida reconstruction of a class III interneuron
that had no synaptic events during carbachol oscillations (like that in
Fig. 5). Bottom right, Single interneuron in the study
that fired out of phase with the carbachol oscillations. The dendrites
were thick and had many spines; axon was primarily in st.
lacunosum-moleculare and st. radiatum, with one branch running into the
granule and molecular layers of the dentate gyrus.
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Interneuron anatomy
St. radiatum interneurons
We were interested in knowing whether the distinct physiologically
defined interneuron classes we identified also exhibited distinct
morphologies. Based on biocytin fills of each interneuron, however, we
were most struck by the general similarity in dendritic and axonal
arbors in interneurons in all classes. Twenty-eight of 42 recorded st.
radiatum interneurons could be identified from the biocytin fills.
These interneurons had three or four primary dendrites whose branches
were nearly always confined within st. radiatum and occasionally
(n = 4) extended one branch into st. oriens (Fig. 7).
Two interneurons extended a dendrite into the hilus and granule cell
layer of the dentate gyrus. Spines were observed on the dendrites of 5 of 28 neurons.
Axons were recovered from 23 filled neurons. Axon arbors most often
projected densely within st. radiatum (20 of 23), and some axon was
recovered within the hilus/CA3c (n = 9), granule cell
layer (n = 2), and molecular layer (n = 2) of the dentate gyrus. Two interneuron axons arborized almost
exclusively within the CA3 pyramidal cell layer, resembling the axons
of basket cells in the CA1 region (Buhl et al., 1994; McBain et al.,
1994; Freund and Buzsaki, 1996; McMahon and Kauer, 1997a,b).
Of 17 biocytin-labeled class I st. radiatum interneurons, 13 had cell
bodies located in CA3b, 2 in CA3a, and 2 in CA2. Of the interneurons
located in CA3b, 11 cells innervated st. radiatum, 3 cells extended
axon into st. lacunosum-moleculare, 3 cells had at least some axon
within the pyramidal cell layer, and 1 preferentially ramified within
st. pyramidale. One interneuron projected axon to the CA1 region and
ramified on both sides of the hippocampal fissure. Of the two class I
interneurons with somas located in CA3a, one innervated st. pyramidale
in CA3b; the other innervated st. radiatum and st.
lacunosum-moleculare. The axon of one interneuron located in CA2
ramified in st. radiatum within CA3a; axon from the second cell was not
recovered. Physiologically, the two neurons that innervated st.
pyramidale resembled other class I interneurons. Eight of nine
interneurons that projected to the dentate gyrus had somas in CA3b and
were defined physiologically as class I interneurons.
Class I cells exhibiting a ramp depolarization before the pyramidal
cell burst were not noticeably different in morphology from class I
cells without the ramp (Fig. 7, top left and
right panels). Although the class I (ramp) interneuron
illustrated in Figure 7 (top right) appears more
elongated in its dendritic tree, with its soma close to the st.
lucidum-st. radiatum border, four other biocytin-filled cells in the
same physiological class had cell bodies either in the middle of st.
radiatum or at the st. radiatum-st. lacunosum-moleculare border. Thus,
despite some apparent differences in the illustrated cells, we did not
find convincing evidence of different gross morphologies between class
I cells with and without the ramp (Fig. 7, top right).
Differences were observed in the dendrites, however; small spines could
clearly be observed on three of five class I cells exhibiting the ramp depolarization, whereas 10 other class I cells appeared spine-free. Recent evidence indicates that a subset of spiny interneurons with cell
bodies and dendrites confined to st. lucidum may be excitatory,
releasing glutamate instead of GABA (Soriano and Frotscher, 1993;
Spruston et al., 1997). Possibly some of the class I ramp interneurons
may fall into this unusual class.
All three class II interneurons filled well with biocytin, and all had
dendrites in st. radiatum and st. lacunosum-moleculare, with axons also
confined to these layers (Fig. 7, middle left). One of
the three had some small spines, whereas the other two were spine-free.
These neurons appeared very similar to most class I interneurons.
Seven of 11 class III cells were filled well with biocytin. The
morphological features of class III interneurons were also similar to
interneurons in the other classes, with the exception of cell body
location. The somas of six of seven interneurons in this class were
located in CA2, the region closest to CA1; the soma of the remaining
neuron was in CA3a. Although biocytin fills were poor for the other
four class III interneurons, at least two of these also had cell bodies
in the CA2-CA3 region. The dendrites projected within st. radiatum and
st. lacunosum-moleculare with a branch from one cell extending into st.
pyramidale (Fig. 7, bottom left). One interneuron had
long, thin, spine-like processes extending from swellings along the
length of the dendrite. Axon was recovered from five class III
interneurons. The axons of all five cells ramified within st. radiatum
and st. lacunosum-moleculare of CA2 and CA3a. Three of five neurons
projected axon well into CA3b, and one cell extended axon into CA1.
Thus, our data indicate that most class I and II interneurons were
located close to CA3b, whereas most class III interneurons were located
at the other end of CA3 closest to area CA1. This difference in cell
location may be responsible for the physiological differences we
report.
St. oriens interneurons
Interneurons with cell bodies in st. oriens were physiologically
characterized as class I interneurons. The dendrites of three of five
biocytin-filled st. oriens cells were confined to that layer, whereas
branches of dendrites from two st. oriens interneurons projected into
st. radiatum as well. The dendrites of one cell had noticeable spines.
Two of five st. oriens interneurons had axons tightly confined near st.
pyramidale (Fig. 7, middle right); two other cells
innervated st. radiatum; one had no recovered axon.
| |
DISCUSSION |
This is the first attempt to classify interneurons in
vitro during rhythmic electrical activity. We used carbachol to
trigger oscillatory activity in area CA3 to assess synaptic connections as they naturally occur during intrinsic activity in the network. Interneuron responses were grouped based on their patterns of excitation and inhibition during carbachol oscillations. A simple scheme of alternating inhibition and excitation, as observed during spindle waves in the thalamus, cannot account for carbachol
oscillations (Bal et al., 1995). Carbachol oscillations are most likely
driven primarily by CA3 pyramidal cells, which excite one another and class I interneurons through multiple collaterals. Class II
interneurons receive more powerful inhibitory connections than
excitatory connections; some of the class I interneurons with axons in
st. radiatum could provide this inhibition. Class III interneurons
probably receive little input from rhythmically active CA3b pyramidal
cells or class I interneurons and might instead act preferentially to
disseminate information received from other brain regions. The
interneuron classes we have identified in vitro could play
specific and distinct roles during a variety of network-driven in
vivo oscillations.
The role of interneurons in carbachol burst generation
GABAA receptors are necessary for maintaining the
repetitive structure of carbachol oscillations (Williams and Kauer,
1997); GABAB receptor blockade has no effect (MacVicar and
Tse, 1989; Williams and Kauer, 1997). GABAA antagonists
both prolong the burst and produce prolonged, irregular interburst
intervals (Williams and Kauer, 1997), most likely by blocking
inhibition delivered by the three interneuron classes we have
identified. A subset of class I (ramp) interneurons fires before the
pyramidal cell burst and may contribute to burst onset by inhibiting
multiple pyramidal cells simultaneously. Class I interneurons may
control burst duration, as they presumably inhibit pyramidal cells
nearly synchronously with excitatory inputs. Even with
GABAA receptors blocked, pyramidal cells are capable of
firing in a bursting pattern, demonstrating that GABAergic interneurons
promote but are not essential for burst initiation (Konopacki and
Golebiewski, 1993; Lukatch and MacIver, 1997).
Class I interneurons are excited during pyramidal cell bursts
CA3 pyramidal cells are a likely major source of excitation for
class I interneurons. A depolarizing GABAA conductance has been described in hippocampal interneurons (Perreault and Avoli, 1989;
Michelson and Wong, 1991, 1994; Dickson and Alonso, 1997); if such a
conductance links class I interneurons together, it may contribute to
interneuron depolarization during the pyramidal cell burst. However,
even when picrotoxin altered the pattern of pyramidal cell bursting,
class I interneurons continued to follow pyramidal cell firing (our
unpublished observations). This suggests that glutamatergic
afferents rather than GABAergic afferents primarily drive rhythmic
excitation of class I interneurons during carbachol oscillations. St.
oriens interneurons fall within class I, based on their robust firing
during each pyramidal cell burst.
The pyramidal cell population can be silenced by firing in
single interneurons
Previous work suggested that interneurons with axons primarily
innervating pyramidal cell bodies are most likely to control synchronous firing in pyramidal cells because the inhibition is delivered close to the site of action potential generation (Miles et
al., 1996). Interneurons with axons localized primarily in st. radiatum
have instead been proposed not to synchronously inhibit pyramidal cells
but instead to control dendritic spike duration (Miles et al., 1996).
Surprisingly, in two recorded class I interneurons a marked quieting of
the pyramidal cell population was clearly observed during interneuron
firing. Axon labeling was recovered for one that showed axon
exclusively in st. radiatum in which it is most likely to innervate
pyramidal cell dendrites. This result indicates that a single class I
interneuron with st. radiatum axon can provide powerful inhibitory
drive to the pyramidal population. Alternatively, we may have recorded
from one of a group of class I interneurons that fire together to
provide synchronous inhibitory drive to pyramidal cells (Michelson and
Wong, 1991, 1994).
Class II interneurons are inhibited by other interneurons
Class II interneurons are only weakly depolarized by carbachol and
are inhibited during the pyramidal cell burst. One likely source of the
inhibitory input is the class I interneurons, which are excited during
pyramidal cell bursts and may in turn release GABA onto their class II
neighbors. Class II cells are also synaptically excited to some extent
by pyramidal cells because when GABAA receptors were
blocked, subthreshold EPSPs were unmasked. It is therefore possible
that class I and class II interneurons represent a continuum along
which class I cells are driven more strongly by excitatory afferents
and more weakly by inhibitory afferents, whereas class II cells exhibit
the opposite. Because class II interneurons were encountered rarely (3 of 42 interneurons), it is difficult to define them confidently;
indeed, we cannot rule out that these cells represent class I
interneurons selectively isolated from excitatory inputs during
slicing.
During in vivo experiments, whereas most interneurons fire
in phase with theta rhythm, a small number of interneurons in st. radiatum reduce their firing rate during theta activity ("theta-off cells") (Buzsaki and Eidelberg, 1983; Colom and Bland, 1987). Other
st. radiatum interneurons in area CA1 are inhibited during sharp-wave
"ripples" in vivo (Freund and Buzsaki, 1996). If these interneurons were encountered in vitro, they might well
exhibit properties like those of class II interneurons, which reduce
their excitability during pyramidal cell activity.
Class III interneurons are only weakly innervated by CA3
pyramidal cells
In contrast to class I interneurons, class III interneurons are
excited only weakly or not at all during oscillations in the pyramidal
cell population. Rhythmic IPSPs, seen in class II interneurons, were
also not observed. Instead, class III interneurons may be driven
exclusively by a population of neurons outside the hippocampus (for
example, septal afferents responsible for theta rhythm), or perhaps by
hippocampal afferents from other regions along the septotemporal axis.
A rarely encountered group of interneurons in st. radiatum of area CA1
is also unaffected during sharp-wave related ripples recorded in
vivo (Freund and Buzsaki, 1996). The class III interneurons we
recorded from in area CA3 may be similarly synaptically connected.
We did observe a preponderance of class III interneurons in CA2
adjacent to area CA1. It may seem that excitatory inputs from CA3b (the
pyramidal cell population responsible for the oscillations) to
interneurons in CA2 might be severed in the slice, thus explaining the
lack of synaptic input to class III cells. We think this unlikely, however, because the much more distant CA1 pyramidal cells are strongly
excited during each carbachol oscillation (Williams and Kauer, 1997).
Our data indicate that CA3b pyramidal neurons (and interneurons of CA3a
and CA3b) do not innervate CA2 interneurons, although Schaffer
collaterals pass through this region on their path to CA1, at least in
the necessarily limited slice preparation.
Functionally different interneurons have similar dendritic and
axonal arbors
Although we identified functionally distinct classes of
interneurons in area CA3, the axons and dendrites of interneurons in
all classes were indistinguishable. A similar homogeneity of CA3
interneuron morphology has been noted previously (McBain and Dingledine, 1993; Jaffe et al., 1997). The expression of
calcium-binding proteins in hippocampal interneurons correlates with
specific afferent inputs from both hippocampal and extrahippocampal
regions (Sloviter and Nilaver, 1987; Freund and Antal, 1988; Toth and Freund, 1992; Freund and Buzsaki, 1996; Gulyas et al., 1996). It will
be of interest to determine whether the three interneuron classes we
have defined may be correlated with these groups.
Interneurons may switch the local network from one rhythm
to another
Our description of functionally distinct interneuron classes
illustrates that under one set of conditions in the network (general excitation by carbachol, rhythmic firing in CA3 pyramidal neurons), local interneurons do not all behave identically. Class I interneurons are most powerfully excited by local pyramidal cells, whereas class II
interneurons are strongly inhibited by other local interneurons. Class
III interneurons are relatively unaffected during carbachol oscillations and may represent a population of interneurons that "sit
out" this particular hippocampal activity.
The interneurons, by virtue of their powerful synchronizing
capabilities and extensive axon arbors, represent logical candidates to
switch the local network from one oscillatory state to another. We
propose that just as the interneuron classes are differentially activated by local afferents, they may also be innervated differently by subcortical and cortical afferents. For example, serotonergic afferents from the raphe nuclei potently and selectively innervate calbindin-positive interneurons, which in turn inhibit local pyramidal cells (Freund et al., 1990). Although the function of this input is not
well defined, serotonin afferents may regulate a form of theta rhythm
in vivo, causing interneurons to fire rhythmically (Leung
and Yim, 1986; Vanderwolf, 1988; Ylinen et al., 1995). Interneurons activated by serotonergic input may be identical with one
of the three interneuron classes defined during carbachol oscillations.
Another example of rhythmic activity can be produced in
vitro in the presence of 4-aminopyridine. Hippocampal interneurons then excite one another directly via GABAA receptors,
producing large synchronous IPSPs in the pyramidal cell population
(Michelson and Wong, 1991). In vivo, interneurons linked in
such a network have been postulated to synchronously activate pyramidal
cells throughout the forebrain at gamma frequency (40-100 Hz), binding neural representations of concurrently perceived information (Bragin et
al., 1995; Buzsaki and Chrobak, 1995; Whittington et al., 1995; Traub
et al., 1996b). Again, one of the functionally defined
interneuron classes may be responsible for this electrical
activity.
In conclusion, the same neuronal wiring diagram can deliver very
different output depending on which interneuron classes are active in a
given situation. It will be of interest to record from the same
interneuron populations during distinct network activities to test the
idea that the classes of interneurons we have identified can switch the
network from one state to another.
| |
FOOTNOTES |
Received Dec. 4, 1997; revised May 11, 1998; accepted May 12, 1998.
Supported by National Institute of Neurological Diseases and Stroke
Grant 30500 and Epilepsy Foundation of America Award to J.A.K. and
National Research Service Award NS09734 to L.L.M. We thank Drs. Susan
Jones, Lawrence Katz, and Richard Mooney for helpful comments on this
manuscript, Dr. Lawrence Katz for use of camera lucida microscope,
Scott Douglas and Andrew Pittman for histology, and Scott Greenberg for
camera lucida drawings.
Correspondence should be addressed to: Julie Kauer, Department of
Neurobiology, Box 3209, Duke University Medical Center, Durham, NC
27710.
Dr. Williams' present address: The Wellcome Trust, Neurosciences, 183 Euston Road, London NW1 2BE England.
| |
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Top
Abstract
Introduction
