Department of Anatomy and Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201
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ABSTRACT |
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Aroniadou-Anderjaska, Vassiliki, Fu-Ming Zhou, Catherine A. Priest, Matthew Ennis, and Michael T. Shipley. Tonic and Synaptically Evoked Presynaptic Inhibition of Sensory Input to the Rat Olfactory Bulb Via GABAB Heteroreceptors. J. Neurophysiol. 84: 1194-1203, 2000. Olfactory receptor neurons of the nasal epithelium send their axons, via the olfactory nerve (ON), to the glomeruli of the olfactory bulb (OB), where the axon terminals form glutamatergic synapses with the apical dendrites of mitral and tufted cells, the output cells of the OB, and with juxtaglomerular (JG) interneurons. Many JG cells are GABAergic. Here we show that, despite the absence of conventional synapses, GABA released from JG cells activates GABAB receptors on ON terminals and inhibits glutamate release both tonically and in response to ON stimulation. Field potential recordings and current-source density analysis, as well as intracellular and whole cell recording techniques were used in rat OB slices. Baclofen (2-5 µM), a GABAB agonist, completely suppressed ON-evoked synaptic responses of both mitral/tufted cells and JG cells, with no evidence for postsynaptic effects. Baclofen (0.5-1 µM) also reversed paired-pulse depression (PPD) of mitral/tufted cell responses to paired-pulse facilitation (PPF), and reduced depression of JG cell excitatory postsynaptic currents (EPSCs) during repetitive ON stimulation. These results suggest that baclofen reduced the probability of glutamate release from ON terminals. The GABAB antagonists CGP35348 or CGP55845A increased mitral/tufted cell responses evoked by single-pulse ON stimulation, suggesting that glutamate release from ON terminals is tonically suppressed via GABAB receptors. The same antagonists reduced PPD of ON-evoked mitral/tufted cell responses at interstimulus intervals 50-400 ms. This finding suggests that a single ON impulse evokes sufficient GABA release, presumably from JG cells, to activate GABAB receptors on ON terminals. Thus GABAB heteroreceptors on ON terminals are activated by ambient levels of extrasynaptic GABA, and by ON input to the OB. The time course of ON-evoked, GABAB presynaptic inhibition suggests that neurotransmission to M/T cells and JG cells will be significantly suppressed when ON impulses arrive in glomeruli at 2.5-20 Hz. GABAB receptor-mediated presynaptic inhibition of sensory input to the OB may play an important role in shaping the activation pattern of the OB glomeruli during olfactory coding.
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INTRODUCTION |
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Olfactory sensory input is
transduced by olfactory receptor neurons (ORNs) in the nasal epithelium
and relayed to the glomeruli of the main olfactory bulb (OB) via the
olfactory nerve (ON). Mammalian ORNs are thought to express a single
odorant receptor (Buck and Axel 1991; Chess et
al. 1994
; Kishimoto et al. 1994
; Zhao et
al. 1998
). A cohort of ORNs expressing the same odorant receptor projects to two (or a few) topographically fixed glomeruli in
the olfactory bulb (Mombaerts et al. 1996
;
Ressler et al. 1994
; Vassar et al. 1994
).
Odorant receptors do not appear to be specific to an odor but rather to
molecular features that may be present in many odorants (Johnson
et al. 1998
). Thus a given odor activates several cohorts of
ORNs (those that respond to the molecular features of the odorant) and
evokes a specific pattern of glomerular activity (Buck
1996
; Friedrich and Korsching 1997
;
Johnson and Leon 1996
; Johnson et al.
1998
; Laurent 1996
). A key issue in olfaction is how the brain computes odors from patterns of glomerular activity. While the glomeruli are the initial stage in this computation (Shepherd 1994
), little is known about the
intraglomerular synaptic mechanisms that regulate glomerular activity.
In the glomeruli, ON terminals form excitatory, glutamatergic synapses
with the apical dendrites of mitral/tufted (M/T) cells (Aroniadou-Anderjaska et al. 1997; Berkowicz et
al. 1994
; Ennis et al. 1996
), the output cells
of the OB, and with juxtaglomerular (JG) interneurons (Bardoni
et al. 1996
; Keller et al. 1998
; Kosaka et al. 1997
; Pinching and Powell 1971b
), many of
which are GABAergic (Gall et al. 1987
; Kosaka et
al. 1985
; Mugnaini et al. 1984
; Ribak et
al. 1977a
). Intraglomerular inhibitory circuits are thought to
play an important role in regulating glomerular activity, but physiological evidence in support of this view is very limited. The
reciprocal synapses of GABAergic JG cells with M/T cells (Hinds 1970
; Pinching and Powell 1971b
; Ribak et
al. 1977a
) suggest that activity in the glomerular dendritic
tufts of M/T cells, evoked by sensory input, may be attenuated via both
feed-forward and feedback inhibitory mechanisms. In addition, recent
evidence suggests that olfactory nerve input to the glomeruli may be
presynaptically inhibited via GABAB receptors.
Thus in the rat olfactory bulb, baclofen, a GABAB
receptor agonist, blocks ON-evoked spiking of mitral cells
(Nickell et al. 1994
) and optically recorded synaptic responses in the glomerular layer (GL), presumably generated by JG
cells (Keller et al. 1998
). Although it could not be
ruled out that these effects were produced by a postsynaptic mechanism, a recent electron microscopy (EM) study demonstrating the presence of
GABAB receptors on ON terminals (Bonino et
al. 1999
) supports the contention that the effects of baclofen
were mediated, at least in part, presynaptically (Keller et al.
1998
; Nickell et al. 1994
). The purpose of the
present study was to investigate the role that
GABAB receptors on ON terminals play in the
function of the glomeruli.
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METHODS |
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Slices of the main olfactory bulb (OB) were prepared from Wistar
rats, 17-22 days old. Details of the slice preparation have been
described previously (Aroniadou-Anderjaska et al. 1997). Briefly, the rats were anesthetized with chloral hydrate (400 mg/kg
body wt) followed by whole-body immersion in ice-cold water. The brain
with the two bulbs was removed and glued to the stage of a Vibroslicer.
Some of the experiments required the lateral olfactory tract (LOT) to
be preserved in the slices (Fig.
1A). To accomplish this, the
brain was positioned so that the bulbs were in approximately the same
horizontal plane with the most ventral part of the forebrain. Slices,
450-500 µm thick, were cut and transferred to an interface chamber,
maintained at 33°C, for field potential and intracellular recordings,
while whole cell recordings were performed in submerged slices at room
temperature. The slices were perfused with artificial cerebrospinal
fluid (in mM: 124 NaCl, 26 NaHCO3, 1.2 NaH2PO4, 3 KCl, 1.3 MgSO4, 2.5 CaCl2, and 10 glucose) at a rate of 1 ml/min in the interface chamber, and 3 ml/min
in the submerged conditions. In some experiments, medium with nominally
zero concentration of Mg2+ was used; this medium
did not include MgSO4.
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Experiments were initiated 1-2 h after the slices were placed in the
chamber. Field potentials were recorded in the GL and, in some
experiments, in the granule cell layer (GCL; see basic OB circuitry in
Fig. 1), using glass pipettes (0.5-2 M) filled with 2 N NaCl. They
were filtered (3 kHz low-pass), and digitized on-line at 15 kHz.
Extracellular stimulation was applied to the ON or the LOT (Fig.
1A) using a dipolar stainless steel electrode (50 µm
diam). Stimulus pulses were 100 µs duration and were applied at 0.05 Hz. Unless indicated otherwise in the results, stimulus intensity was
adjusted to evoke a field potential of 1.5-2.5 mV in the GL by ON
stimulation (10-60 µA), or in the GCL by LOT stimulation (80-150
µA). This amplitude range was 40-70% of the maximum peak amplitude
of ON-evoked GL field potentials, and 60-80% of the maximum amplitude
of LOT-evoked GCL field potentials.
One set of experiments required recordings of laminar field potential
profiles, which were analyzed with the current source density (CSD)
method as described previously (Aroniadou-Anderjaska et al.
1999a). Briefly, the approximation formula for one-dimensional CSD (Freeman and Nicholson 1975
) was used. The validity
of one-dimensional CSD in the main OB, along the axis perpendicular to
the laminae, has been shown (Aroniadou-Anderjaska et al.
1999a
). Spatial resolution and differentiation grid were 100 and 200 µm, respectively. Conductivity gradients across laminae have
no significant influence on the general features of the laminar CSD
distribution (Martinez 1982
), and therefore they were
considered negligible.
Conventional methods were used for intracellular recordings from mitral
cells, using the Axoclamp-2A amplifier (Axon Instruments) in the bridge
mode. Glass pipettes (50-90 M) were filled with potassium acetate
(4 M). For whole cell recordings from juxtaglomerular cells, patch
pipettes were filled with (in mM) 135 KCl, 10 HEPES, 2 Mg-ATP, 0.2 Na-GTP, and 0.5 EGTA; pH and osmolarity were adjusted to 7.3 and 280 mOsm, respectively. Electrical signals were recorded using an
Axopatch-200B amplifier (Axon Instruments) with the low-pass filter set
at 5 kHz. Juxtaglomerular cells were visualized with an Olympus BX50WI
upright microscope equipped with a ×60 water immersion lens and DIC
optics. The recorded cells were probably the periglomerular type
(GABAergic juxtaglomerular cells) because they had small soma size and
high-input resistance. All data acquisition and analysis, including the
CSD analysis, were performed with the pClamp software (Axon
Instruments). In the results, group data are presented as means ± SE.
The following drugs were used: R(+) baclofen hydrochloride (referred to
as baclofen), a selective GABAB receptor agonist
(Research Biochemicals International); CGP-35348 (Olpe et al.
1990) or CGP-55845A (Frostl et al.
1992
), specific, competitive
GABAB receptor antagonists (gift from NOVARTIS
Pharma); 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a
kainate/
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptor antagonist (Research Biochemicals International); D-2-amino-5-phosphonovalerate (APV), an
N-methyl-D-aspartate (NMDA) receptor antagonist
(Research Biochemicals International); and bicuculline methchloride, a
GABAA receptor antagonist (Research Biochemicals
International). To prepare stock solutions, all drugs were dissolved in
dH2O, except for CNQX, which was dissolved in DMSO (final concentration of DMSO in the slice medium was 0.01%, vol/vol). All drugs were delivered by bath application.
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RESULTS |
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Pharmacological activation of GABAB receptors
EFFECTS OF BACLOFEN ON ON-EVOKED RESPONSES OF M/T CELLS.
In the first series of experiments, our aim was to obtain solid
physiological evidence for the presence of functional
GABAB receptors on ON terminals. First, we
examined the effects of GABAB receptor activation
by baclofen on the ON-evoked responses of M/T cells. Single pulses to
the ON evoke a two-component field excitatory postsynaptic potential
(EPSP) in the GL (Fig. 2A). This field potential reflects predominantly synaptic currents in the
apical dendrites of M/T cells and is mediated by glutamate receptors
(Aroniadou-Anderjaska et al. 1997,
1999a
). The fast component (N1) is mediated by
kainate/AMPA receptors, whereas most of the slow component (N2) depends
on NMDA receptor activation. Bath application of 5 µM baclofen
reduced both the N1 and N2 components of the field EPSP (Fig.
2B). The peak amplitude of N1 was reduced by 79.6 ± 5.6% (mean ± SE, n = 10). These effects were
reversed after washing-out baclofen.
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SITE OF BACLOFEN ACTION. The dramatic effect of baclofen on ON-evoked responses of M/T cells suggested that baclofen may act on the ON terminals and inhibit glutamate release. The apparently minor postsynaptic effects on mitral cells were consistent with this possibility; however, if GABAB receptors on mitral cells were present exclusively on the apical dendritic tufts, postsynaptic effects of baclofen may be difficult to detect with somatic recordings.
To determine whether baclofen acted presynaptically, first we examined how baclofen affects responses to paired-pulse stimulation of the ON. When two identical stimuli are delivered at various interstimulus intervals (ISI), the first pulse may produce depression (paired-pulse depression, PPD) or facilitation (PPF) of the response to the second pulse. An important factor determining whether PPD or PPF is produced is the probability of transmitter release in response to the first (conditioning) pulse (Debanne et al. 1996
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Activation of GABAB receptors by endogenous GABA
To investigate whether GABAB receptors on ON
terminals play a role in the function of the OB, we next examined
whether these receptors are activated by endogenous GABA. The origin of
endogenous GABA in the glomeruli is a population of JG cells, the
GABAergic periglomerular (PG) cells (Gall et al. 1987;
Kosaka et al. 1985
; Mugnaini et al. 1984
;
Ribak et al. 1977a
). PG cells receive excitatory input
from the ON (present data and Bardoni et al. 1996
;
Heyward et al. 1997
; Keller et al. 1998
)
and from the dendrites of M/T cells (Bardoni et al.
1996
). Ultrastructural studies have revealed symmetrical
synapses from PG cells to the dendrites of M/T cells and other PG
cells, but no evidence has been found for synapses from PG cells onto
ON terminals (Hinds 1970
; Pinching and Powell 1971b
; Ribak et al. 1977b
).
To determine whether, despite the lack of anatomical synapses, GABA released from PG cells gains access to GABAB receptors on ON terminals, we investigated the effects of the GABAB antagonists, CGP-35348 (0.5-1 mM) and CGP-55845A (10 µM), on glomerular field EPSPs evoked by paired-pulse ON stimulation. The GABAB antagonists increased both the conditioning and the test responses. The effect on the test responses was significantly greater, resulting in reduction of PPD, or reversal of PPD to PPF. An example is shown in Fig. 7A, and group data from 10 slices where CGP-35348 was used are shown in Fig. 7B. The reduction in PPD by CGP-35348 was significant at interstimulus intervals from 50 to 400 ms (P < 0.02, paired t-test). These results suggest that GABA released from PG cells in response to the conditioning pulse of the ON activates GABAB receptors on ON terminals and thus reduces the M/T cell response to the test pulse.
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The responses to the conditioning pulses, and responses to single-pulse ON stimulation, were also increased by the GABAB antagonists (Fig. 7, A and C). The peak amplitude of N1 increased by 30%, from 2.0 ± 0.13 mV, in control medium, to 2.6 ± 0.18 mV, after application of either GABAB antagonist (n = 19, P < 0.0004, paired t-test). Figure 7C shows the time course of the effect of CGP-55845A on conditioning and test responses evoked at an interstimulus interval of 100 ms (group data from 6 slices). The latency to peak amplitude of N1 ranges from 9 to 12 ms, whereas ON-evoked activation of GABAB receptors on ON terminals takes effect after 30 ms post-ON stimulation (Fig. 7B). Therefore the increase of the conditioning responses by the GABAB antagonists cannot be due to the same mechanism as the test responses, i.e., blockade of polysynaptically mediated activation of GABAB receptors; rather, this increase suggests that the GABAB antagonists blocked tonic activation of GABAB receptors. Thus taken together, these results show that GABAB receptors on ON terminals are tonically activated by ambient concentrations of extracellular GABA, and are further activated by GABA release from PG cells in response to a single stimulus pulse applied to the ON.
M/T to granule cell transmission is not affected by baclofen or CGP-35348
The lateral dendrites of M/T cells release glutamate onto the
dendrites of granule cells producing a negative field EPSP in the
external plexiform layer (EPL) and a corresponding positive field
potential in the GCL (Rall and Shepherd 1968). The EPL
field EPSP evoked by ON stimulation influences to some extent the fast, kainate/AMPA component of the GL field EPSP, increasing its amplitude and broadening its time course (Aroniadou-Anderjaska et al.
1997
, 1999a
). Thus if there were
GABAB receptors on the lateral dendrites of M/T
cells, then the effects of the GABAB antagonists
on the GL field EPSP (Fig. 7) could, in part, be due to a change in the EPL field EPSP. To investigate this possibility we delivered stimulus pulses alternately to the LOT and to the ON, while recording granule cell field responses in the GCL. Baclofen (up to 50 µM) had no effect
on the LOT-evoked field potential, although it completely suppressed
the ON-evoked GCL field potential (n = 3, Fig.
8A). Similarly, CGP-35348 had
no effect on PPD of the LOT-evoked, GCL field potential, although it
reduced PPD of the ON-evoked GCL field potential (ISIs 50, 100, 150, and 200 ms; n = 4, Fig. 8B). Thus baclofen
and CGP-35348 do not affect transmission from M/T to granule cells; the
effects of these drugs on the ON-evoked GCL field potential were due to
activation of GABAB receptors on the ON
terminals. These results allow us to conclude that the effects of the
GABAB antagonists on the ON-evoked, GL field EPSP (Fig. 7) are solely due to an action in the GL.
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DISCUSSION |
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In the present study, it was found that 1) baclofen suppresses synaptic transmission from the ON to M/T cells and JG cells by reducing glutamate release from the ON axon terminals, and 2) GABAB receptors on ON terminals are activated by endogenous GABA, both tonically and in response to ON stimulation.
Evidence for functional GABAB receptors on ON terminals
Functional GABAB receptors are heteromeric
complexes of the GABABR1 subunit, which exists in
two splice variants, R1a and R1b, and the GABABR2
subunit (Kaupmann et al. 1998; Kuner et al. 1999
). Combination of the GABABR1 with
the GABABR2 appears to be essential for transport
to the membrane and full functionality of the receptor (Couve et
al. 1998
; Kaupmann et al. 1998
; White et
al. 1998
). In the rat OB, the glomeruli have the highest
concentration of GABAB receptors as determined by
radioligand autoradiographic studies (Bowery et al.
1987
; Chu et al. 1990
) and by
immunohistochemical localization of the
GABABR1a/b subunit (Margeta-Mitrovic et
al. 1999
). Combined electron microscopy and immunohistochemical
staining for GABABR1 revealed that the dense
labeling of the glomeruli is due to the presence of
GABAB receptors on ON terminals and in the somata
of periglomerular cells (Bonino et al. 1999
). In addition, ORNs in the nasal epithelium label uniformly with antiserum to GABABR1 (Aroniadou-Anderjaska et al.
1999c
), suggesting that all ORNs express
GABAB receptors, which may be transported to their axon terminals. Although it remains to be determined whether ORNs
also express the GABABR2 subunit, the
functionality of GABAB receptors on the axon
terminals of the ORNs was suggested by previous studies (Keller
et al. 1998
; Nickell et al. 1994
), and is
clearly demonstrated by the present data. Thus it has been shown that baclofen blocks ON-evoked mitral cell spiking (Nickell et al. 1994
) and optical signals generated by JG cells (Keller
et al. 1998
). It was suggested that the dramatic effects of
baclofen may imply, at least in part, a presynaptic action
(Keller et al. 1998
; Nickell et al.
1994
). The present study provides solid support of this view,
and further shows that baclofen blocks ON input to the OB by a
presynaptic action alone. Thus ON-evoked synaptic responses of both
glomerular targets of the ON, the M/T cells, and JG cells, were
completely suppressed by baclofen, with no concomitant postsynaptic
changes in input resistance or holding current. The small
hyperpolarization of mitral cells following application of baclofen
could be due to blockade of tonic activation of these cells by
glutamate release from ON terminals. Additional evidence that baclofen
can block ON transmission by acting exclusively on ON terminals comes
from the experiment where an NMDA current sink was evoked in the apical
dendrites of M/T cells via two independent pathways (ON and LOT
stimulation), and only the ON-evoked sink was suppressed by baclofen
(Fig. 5).
The mechanism by which baclofen suppressed transmission from the ON
appeared to be a reduction in the probability of glutamate release. In
a paired-pulse paradigm, the higher the probability of transmitter
release during the conditioning pulse, the smaller the response to the
test pulse will be (larger PPD) (Debanne et al. 1996;
Manabe et al. 1993
; Thomson et al. 1993
).
Baclofen reversed PPD of the ON-evoked responses of M/T cells to PPF
(Fig. 4) and reduced depression of the JG cell EPSCs during repetitive
ON stimulation (Fig. 6B), effects that are consistent with a
decreased probability of glutamate release from ON terminals. As shown
in other CNS areas, this could be effected by a reduction of
Ca2+ influx into the terminals (Dolphin
1995
; Lambert et al. 1991
; Mott and Lewis
1994
; Takahashi et al. 1998
; Wu and
Saggau 1995
, 1997
), and/or a direct effect on
the release process downstream to Ca2+ influx
(Dittman and Regehr 1996
; Jarolimek and Misgeld
1997
; Scanziani et al. 1992
). In turtle
olfactory nerve terminals, baclofen was recently shown to reduce
Ca2+ influx (Wachowiak and Cohen
1999
).
The present data do not provide evidence for direct effects of baclofen
on JG cells or mitral cells, since there were small or no postsynaptic
changes when ON-evoked responses of M/T cells and JG cells were
completely suppressed by baclofen. In addition, the lack of any effects
of baclofen or CGP-35348 on synaptic transmission from M/T cells to
granule cells (Fig. 8) suggests that glutamate release from the lateral
dendrites of M/T cells is not modulated by GABAB
receptors. Although both JG cells and mitral cells stain with antiserum
to GABABR1a/b (Bonino et al. 1999;
Margeta-Mitrovic et al. 1999
), there are no cells in the
rat OB expressing significant levels of the
GABABR2 subunit, as determined by in situ
hybridization (Kaupmann et al. 1998
). Thus JG cells and
mitral cells may not have functional GABAB
receptors, and the GABAB receptor subunits that
these cells express may not be transported to synaptic sites. Consistent with the latter, there is minimal staining for
GABABR1a/b in the EPL (Margeta-Mitrovic et
al. 1999
), where the lateral dendrites of mitral cells receive
the vast majority of GABAergic synaptic inputs. In addition,
Bonino et al. (1999)
did not detect
GABABR1 immunoreactivity on dendrites of either
JG cells or M/T cells in the glomerular layer. Thus it is possible that
in the rat OB only the GABAB receptors on ON
terminals are fully functional. This, however, requires further investigation.
Tonic and synaptically evoked activation of GABAB receptors by endogenous GABA
In the present study, GABAB antagonists increased responses of M/T cells evoked by single-pulse ON stimulation, suggesting that ambient levels of extracellular GABA tonically activate GABAB receptors on ON terminals. In addition, GABAB antagonists reduced the depression of test responses of M/T cells to paired-pulse stimulation of the ON, indicating that a single stimulus pulse to the ON (the conditioning pulse) elevates extracellular GABA above tonic levels, to further activate GABAB receptors on ON terminals.
The source of endogenous GABA in the glomeruli of the OB is a
subpopulation of JG cells, the PG cells (Gall et al. 1987;
Kosaka et al. 1985
; Mugnaini et al. 1984
;
Ribak et al. 1977a
). PG cells are activated by ON
stimulation (present data and Bardoni et al. 1996
;
Heyward et al. 1997
; Keller et al. 1998
);
they form dendrodendritic synapses with M/T cells and other JG cells,
but they do not form synapses with ON terminals (Hinds
1970
; Pinching and Powell 1971b
; Ribak et
al. 1977a
). In most CNS areas, GABAergic neurons do not form
synapses with excitatory terminals. However,
GABAB heteroreceptors can be activated by low
concentrations of extrasynaptic GABA, due to their high affinity for
GABA (Sodickson and Bean 1996
; Yoon and Rothman
1991
). In the hippocampus (Isaacson et al. 1993
) and cerebellum (Dittman and Regehr 1997
), extrasynaptic
GABA reaches sufficiently high levels to activate
GABAB heteroreceptors only following
high-frequency stimulation of GABAergic neurons. However, tonic
activation of GABAB heteroreceptors has been
reported in other CNS areas (Emri et al. 1996
;
Kombian et al. 1996
).
The more effective activation of GABAB
heteroreceptors in the OB, compared with the hippocampus or cerebellum,
may be due to differences between these structures in the proximity of
GABA release sites to GABAB heteroreceptors,
and/or the proximity of GABA uptake systems to GABA release sites and
GABAB heteroreceptors. GABA transporters are
located on GABAergic neurons and glia cells (Hertz
1979). In the OB, the dendrodenritic synapses between PG and
M/T cells are partially enclosed by glia processes (Chao et al.
1997
; Kasowski et al. 1999
). Thus GABA released
from PG cells at dendrodendritic synapses with M/T cells would probably
have to escape the glia barrier to reach GABAB
receptors on ON terminals. Although this cannot be excluded, another
possibility is that GABA is released from nonsynaptic dendritic sites
of PG neurons that are close to the ON terminals. Consistent with this,
synaptic vesicles are present in some PG cell dendrites apposed to
olfactory nerve terminals that are immunopositive for
GABAB receptors (Bonino et al.
1999
). In addition, there are only few glial processes close to
axodendritic synapses formed by the ON (Chao et al.
1997
; Kasowski et al. 1999
), which may
facilitate the build-up of extrasynaptic GABA. The glomerular
inhibitory interactions suggested by the present and previous findings
are summarized schematically in Fig. 9.
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Relation to the function of the OB
Olfactory information is thought to be encoded by specific
patterns of glomerular activity (Buck 1996;
Friedrich and Korsching 1997
; Guthrie et al.
1993
; Johnson and Leon 1996
; Johnson et
al. 1998
; Laurent 1996
; Shepherd
1994
; Stewart et al. 1979
). The present findings
suggest that GABAB receptor-mediated presynaptic
inhibition of ON input to the glomeruli may play an important role in
determining both spatial and temporal components of glomerular
activation. Tonic activation of GABAB receptors
on ON terminals may serve to filter out weak ("noise") signals.
This may sharpen the spatial pattern of active glomeruli and facilitate
detection of the predominant odor. Strong signals are likely to
activate more PG cells and evoke stronger inhibition of subsequent ON
inputs. This is likely to affect the temporal patterns of glomerular
activation in response to repetitive sniffs. During repetitive
sniffing, presynaptic GABAB inhibition may adjust
the level of glomerular excitation, as a function of sniffing
frequency. Our PPD data predict that GABAB
presynaptic inhibition will be most effective in inhibiting signals
arriving at 100- to 200-ms intervals (5-10 Hz), the dominant frequency
during exploratory sniffing (Komisaruk 1970
;
Macrides and Chorover 1972
; Welker 1964
).
However, a novel odor occurring within such a sniffing bout would
activate different glomeruli and, initially, would not be inhibited to
the same degree. Thus frequency-dependent GABAB
receptor-mediated inhibition of input to the glomeruli may enhance
detection of novel stimuli.
The extent to which presynaptic GABAB inhibition
influences glomerular excitation may vary dynamically, as centrifugal
inputs to the glomeruli may alter PG cell excitability (Pinching
and Powell 1971c; Shipley et al. 1996
). In
addition, there is evidence for anatomical connections between
glomeruli (Cajal 1911
; Pinching and Powell
1971a
). If these connections affect GABA release, then GABAB receptors on ON terminals could mediate
interglomerular influences on glomerular activity patterns. Finally,
GABAB receptors on ON terminals could play a role
in induction of long-term potentiation at the first synapse in the
olfactory system (Ennis et al. 1998
).
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ACKNOWLEDGMENTS |
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We thank Dr. Nevin A. Lambert for valuable discussions. We also thank Drs. Asaf Keller, Scott M. Thompson, and Michael Meredith for critical review of the manuscript. We are grateful to Dr. Wolfgang Froestl and Novartis Pharma Inc. for the generous gift of the GABAB antagonists.
This work was supported by National Institutes of Health Grants DC-00347, DC-03195, DC-02173, and NS-36940. F.-M. Zhou was supported in part by a Young Investigator Award from the National Alliance for Research in Schizophrenia and Depression.
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FOOTNOTES |
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Present address and address for reprint requests: V. Aroniadou-Anderjaska, Dept. of Psychiatry, Uniform Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814 (E-mail: vanderjaska{at}usuhs.mil).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 3 February 2000; accepted in final form 24 May 2000.
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REFERENCES |
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