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The Journal of Neuroscience, December 1, 2000, 20(23):8750-8753
Exacerbation of Noise-Induced Hearing Loss in Mice Lacking the
Glutamate Transporter GLAST
Nobuhiro
Hakuba1,
Kenichiro
Koga1,
Kiyofumi
Gyo1,
Shin-ichi
Usami2, and
Kohichi
Tanaka3
1 Department of Otolaryngology, Ehime University School
of Medicine, Ehime 791-0295, Japan, 2 Department of
Otorhinolaryngology, Hirosaki University School of Medicine, Hirosaki
036-8562, Japan, and 3 Department of Molecular
Neuroscience, Medical Research Institute, Tokyo Medical and Dental
University, Bunkyo-ku, Tokyo 113-8519, Japan
 |
ABSTRACT |
Acoustic overstimulation is one of the major causes of hearing
loss. Glutamate is the most likely candidate neurotransmitter for
afferent synapses in the peripheral auditory system, so it was proposed
that glutamate excitotoxicity may be involved in noise trauma. However,
there has been no direct evidence that noise trauma is caused by
excessive release of glutamate from the inner hair cells (IHCs) during
sound exposure because studies have been hampered by powerful glutamate
uptake systems in the cochlea. GLAST is a glutamate transporter highly
expressed in the cochlea. Here we show that after acoustic
overstimulation, GLAST-deficient mice show increased accumulation of
glutamate in perilymphs, resulting in exacerbation of hearing loss.
These results suggest that GLAST plays an important role in keeping the
concentration of glutamate in the perilymph at a nontoxic level during
acoustic overstimulation. These findings also provide further support
for the hypothesis that IHCs use glutamate as a neurotransmitter.
Key words:
glutamate transporter; excitotoxicity; noise trauma; inner hair cell; knock-out mouse; supporting cell
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INTRODUCTION |
Acoustic trauma is one of the major
causes of hearing loss. Exposure to an intense, loud noise causes
afferent dendrite swelling below inner hair cells (IHCs) as well as
mechanical damage to outer hair cells (OHCs) (Robertson, 1983 ; Saunders
et al., 1985). Because glutamate is the most likely candidate
neurotransmitter for IHC-auditory nerve synapses (Ottersen et al.,
1998) and the noise-induced dendrite damage is very similar to that
seen after exposure of the cochlea to glutamate receptor agonists (Puel
et al., 1991; Puel, 1995), it has been suggested that noise-induced hearing loss may be caused, in part, by glutamate excitotoxicity. However, no previous studies directly examined the excess release of
glutamate during sound exposure and its correlation with the functional
impairment because powerful glutamate uptake systems rapidly remove
synaptically released glutamate from the extracellular space. To date,
five subtypes of Na+-dependent glutamate
transporters, abbreviated as GLT-1, GLAST, EAAC1, EAAT4, and EAAT5,
have been cloned (Arriza et al., 1997; Kanai, 1997; Tanaka, 2000).
Previous studies demonstrate that GLAST is present in the rat and
guinea pig cochlea (Li et al., 1994; Furness and Lehre, 1997). Thus,
GLAST-deficient mice provide an in vivo model for studying
an excitotoxic mechanism producing noise-induced hearing loss (Harada
et al., 1998; Watase et al., 1998; Watanabe et al., 1999). We now
report that after noise overstimulation, GLAST-deficient mice exhibit
increased accumulation of glutamate in perilymphs, resulting in
exacerbation of hearing loss.
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MATERIALS AND METHODS |
Immunohistochemistry. The animals were deeply
anesthetized with sodium pentobarbital (50 mg/kg, i.p.). Before
systemic transcardial perfusion with 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.25, the same fixative was injected
through the tympanic membrane. The temporal bones were removed
immediately after perfusion and post-fixed with 4% paraformaldehyde at
4°C for 3 hr. They were then incubated in 7% EDTA (in
H2O) for decalcification for 2 weeks. Serial
cryostat sections (15 µm thick) were cut and placed on silane-coated
slides. Immunocytochemical staining of GLAST was performed by an
indirect immunofluorescence method. The specimens were incubated with
the following solutions: (1) rabbit polyclonal anti-GLAST antibody (4 µg/ml, kindly provided by Dr. N. C. Danbolt, University of
Oslo, Norway, in PBS with 0.3% Triton X-100), overnight at 4°C; (2)
biotinylated anti-rabbit IgG (Vector Laboratories, Burlingame, CA),
overnight at 4°C; and (3) streptavidin-fluorescein isothiocyanate
(FITC) (Amersham, Arlington Heights, IL), 2 hr at room temperature. For
double staining of GLAST and glutamine synthetase, the specimens were
incubated with the following solutions: (1) a mixture of rabbit
polyclonal anti-GLAST antibody (A522, raised against a synthetic
peptide corresponding to amino acids 522-541) (Lehre et al.,
1995), and mouse monoclonal anti-glutamine synthetase (MAB302;
Chemicon, Temecula, CA) diluted with 0.3% Triton X-100, overnight at
4°C; (2) a mixture of the secondary antibodies, biotinylated
anti-rabbit IgG (Amersham) and FITC-conjugated goat anti-mouse IgG
(Amersham), overnight at 4°C; and (3) streptavidin Texas Red
(Amersham), 2 hr at room temperature. The antibody dilutions were 4 µg/ml (A522), 1:1000 (MAB302), or 1:100 (secondary
antibodies). The specimens were examined with a confocal scanning
microscope (Olympus Optical, Tokyo, Japan) equipped with the
appropriate filter combinations. Specificity of anti-GLAST antibody has
been verified previously (Lehre et al., 1995). Four adults (12-16
weeks old) of each genotype were examined.
Microdialysis. Mice were anesthetized with a mixture of
nitrous oxide/oxygen (1:1) gas and 3% halothane. During the
experiment, body temperature was kept at 36-37°C by a heating lamp.
In the right ear, the otic bulla was exposed by a retroauricular
incision. A small hole, 0.3 mm in diameter, was drilled into the basal
turn of the cochlea, and a probe with a dialysis membrane (Eicom,
Kyoto, Japan) 1 mm in length and 0.22 mm in diameter was positioned in the tympanic scala through the hole using a micromanipulator. The probe
was sealed and fixed with dental cement. The microdialysis system was
perfused with Ringer's solution at a flow rate of 0.6 µl/min using a
microinfusion pump (BRC, Nagoya, Japan). The samples of the dialysate,
3 µl each, were sequentially collected every 5 min in sampling tubes
in an ice bath: 4 samples before noise exposure, 6 samples during noise
exposure, and 24 samples after noise exposure. The concentration of
glutamate was measured by an enzymatic cycling procedure, as reported
by Mitani et al. (1994). Eight adults (12-16 weeks old) of each
genotype were examined.
Auditory brainstem responses. Auditory brainstem responses
(ABRs) were obtained from mice anesthetized with a mixture of nitrous oxide/oxygen (1:1) gas and 3% halothane. Responses were differentially recorded between subcutaneous stainless steel electrodes at the vertex
(active) and mastoid (reference), and the lower back served as ground.
Testing was performed in a sound-attenuated box. The ABRs, in response
to the sound of clicks, were recorded using a signal processor
(NEC Synax 1200, Tokyo, Japan). The average of 300 responses was taken.
Threshold is defined as the intensity level at which an ABR wave I with
an amplitude of 0.05 µV was seen in two averaged runs. Eight adults
(12-16 weeks old) of each genotype were examined.
Sound overexposure. The acoustically traumatizing stimulus
[4 kHz continuous pure tone at 105 dB sound pressure level (SPL) for
30 min] was produced by a National VP-7421A signal generator (Matsushita Electric, Tokyo, Japan) and amplified by a Kenwood KA-990-D amplifier (Kenwood, Tokyo, Japan). Intense sound was delivered from a Fostex FT96H loudspeaker (Fostex) in front of the head
of the anesthetized animal in a sound exposure box (40 × 15 × 15 cm) under anesthesia. One animal was exposed at a time.
Histological analysis. The cochleae were perfused (10 min)
in situ with 2.5% glutaraldehyde in 0.1 M phosphate buffer. The animals were then killed,
and the cochleae were quickly removed and immersed in the same fixative
for 8 hr at 4°C. They were post-fixed in 2%
OsO4 (2 hr), dehydrated in ethanol, and embedded
in epoxy resin. Ultrathin sections were made from the basal turn and
then counterstained with uranyl acetate and lead citrate before being observed under a transmission electron microscope (Hitachi H800).
We quantified the loud sound-induced damage to fibers by counting the
number of swollen dendritic terminals in contact with the IHCs at
presound exposure and at 5 and 120 min after sound exposure. The
criteria for swollen dendritic terminals were as follows: (1) the
appearance of clear cytosol and the presence of a rounded, regular
membrane. (2) The contrast of the intracellular content was weaker than
that of IHCs. For the size, we measured the length along the long axis
of dendritic terminals in four control cochleae with no treatment. The
three largest oval-shaped dendritic terminals were then chosen from
each section. The average length along the long axis of these dendritic
terminals was 1.2 µm. (3) In cochleae after sound exposure, dendritic
terminals with a length of <1.2 µm were not counted as swollen. Four
adults (12-16 weeks old) of each genotype were examined.
| |
RESULTS |
Localization of a glutamate transporter, GLAST, in the
mouse cochlea
GLAST was found in the region of the IHCs, forming flask-shaped
outlines with the shape of the IHC body and around the spiral ganglion
cells (Fig. 1A). There
was no significant staining in the region of the OHCs, in agreement
with previous results (Furness and Lehre, 1997). GLAST was also found
in the fibrocytes in the limbus and the spiral ligament (Fig.
1A). In GLAST-deficient mice, however, there is no
significant immunoreactivity, despite morphologically normal appearance
(Fig. 1B). From the immunocytochemistry result in
Figure 1A, it is difficult to determine the cellular
origin of the GLAST immunoreactivity. To address this question, we
performed a double-labeling experiment using GLAST antibody together
with glutamine synthetase (GS) antibody that has been shown to be a specific marker for the supporting cells (Takumi et al., 1997; Ottersen
et al., 1998). Superimposed images of GLAST and GS show that green
areas (indicating GS) were found evenly in the supporting cells,
whereas orange areas (indicative of colocalization) and red areas
(indicating GLAST) occurred along the margins of these cells (Fig.
1C,D), indicating that GLAST is localized in the
supporting cells around the IHCs.
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Figure 1.
Images by confocal laser scanning microscopy.
A, B, Immunofluorescence for GLAST in the cochlea in
wild-type (A) and GLAST-deficient
(B) mice. The interference image is superimposed
on the immunofluorescent image. C, Double
immunofluorescence for GLAST (red, rabbit antibody) and
glutamine synthetase (green, mouse) in the
cochlea in wild-type mice. Green areas (indicating
single labeling for glutamine synthetase) occur in the central parts of
the supporting cells, whereas yellow areas (indicative
of colocalization) occur along the margins of these cells.
D, A bright field of C.
IHC, Inner hair cell; OHC, outer hair
cell; LIM, limbus; SG, spiral ganglion;
TM, tectorial membrane; BM, basilar
membrane. Scale bars: A, B, 100 µm;
C, D, 50 µm.
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Monitoring of glutamate concentration in
noise-stimulated perilymph
To examine the role of GLAST in glutamate clearance, we measured
the basal concentration and time course of free glutamate in perilymphs
during and after noise exposure using a microdialysis technique (Hakuba
et al., 1997). Before noise exposure, the basal glutamate level in the
mutant mice [0.90 ± 0.06 pmol/µl (mean ± SEM);
n = 8] was significantly elevated in comparison with
the wild-type mice (0.58 ± 0.07 pmol/µl; n = 8)
(p < 0.01, t test) (Fig.
2). Moreover, a significant increase in
glutamate level was observed during and after exposure in the mutant
mice (p < 0.05), whereas no significant
increase in glutamate level was observed in the wild-type mice (Fig.
2). These results indicate that GLAST is an important determinant of
glutamate clearance in the cochlea and that glutamate is the most
likely candidate neurotransmitter for the afferent hair cell
synapses.
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Figure 2.
Changes in glutamate concentration in the
perilymph before, during, and after 105 dB sound exposure in wild-type
(n = 8, open circles) and
GLAST-deficient mice (n = 8, closed
circles). Data are mean ± SEM (bars)
values.
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The effects of noise trauma in GLAST-deficient mice
To test the excitotoxic nature of acoustic trauma, we compared
functional and structural damage after exposure to a 4 kHz pure tone at
a 105 dB SPL for 30 min in wild-type and mutant mice. Functional damage
was estimated using ABRs. The ABR thresholds of mutant mice
(33.75 ± 2.46 dB SPL; n = 8) were slightly but significantly higher than thresholds of wild-type mice (23.75 ± 1.57 dB SPL; n = 8) (p < 0.005, t test) before exposure. Amplitudes of the five principal
waves of mutant mice were decreased, although no change in latencies of
all five waves could be detected (data not shown). Thus, although GLAST
is expressed in astrocytes of brainstem structures (the cochlear
nucleus and inferior colliculus), it is likely that the ABR threshold
elevation of mutant mice is of peripheral origin. After sound exposure,
the homozygous mutants displayed a significant rise in ABR thresholds
and a significant delay in the recovery of the ABR thresholds (Fig.
3). Histologically, we examined sections
from the basal turn of the cochlea, corresponding to a frequency of 4 kHz (Greenwood, 1990). No excitotoxic damage (i.e., the afferent
dendrite swelling below IHCs) was observed in mutant mice at presound
exposure (Fig. 4B).
Noise exposure acutely produced afferent nerve terminal swelling at the
IHC in both wild-type and mutant mice (Fig. 4, Table
1). Two hours after exposure, the
morphological appearance of the IHC and dendrite region had returned to
almost normal in wild-type mice (Fig. 4E), whereas
the swelling was still observed in mutant mice (Fig.
4F). Figure 4 shows cross-sections of IHCs taken from
typical animals from the two groups (wild-type and mutant). All eight
cochleae from two groups of four mice each used for histological
analysis showed almost similar results. These results indicate that
GLAST-deficient mice show a significant increase in noise-induced
hearing loss because of the exacerbation of dendrite damage, confirming
the excitotoxic nature of noise-induced hearing loss.
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Figure 3.
Shifts of the ABR thresholds after 105 dB sound
exposure in wild-type (n = 8, open
circles) and GLAST-deficient (n = 8, closed circles) mice. Data are mean ± SEM
(bars) values. (* p < 0.005; **
p < 0.05; data were analyzed by t
test).
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Figure 4.
Effect of 105 dB sound exposure on the auditory
dendrites below the IHCs in wild-type (A,
C, E) and GLAST-deficient
(B, D, F) mice.
Typical transmission electron micrographs showing IHC region, presound
exposure (A, B), 5 min (C, D), and 120 min (E, F) after sound exposure.
Arrows indicate massive swelling of structures in
dendrite region. All micrographs are taken from the basal turn of the
cochlea. Scale bars, 2 µm.
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Table 1.
Means and SEs of the number of swollen dendritic terminals
before and after sound exposure in wild-type and GLAST-deficient mice
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DISCUSSION |
Our results suggest that GLAST plays a neuroprotective role
against noise-induced hearing loss. Glutamate neurotoxicity is implicated in a number of pathological states, such as ischemia, aminoglycoside antibiotics-induced hearing loss, neural presbycusis, and certain forms of peripheral tinnitus (Puel, 1995; Basile et al.,
1996). Pujol et al. (1993) reported a protective effect of piribedil, a
D2 dopamine receptor agonist, against the radial dendritic swelling
induced by transient ischemia (Pujol et al., 1993). Accordingly,
bromocriptine may serve as a prototype for the development of new
therapeutic agents for these pathological conditions because
bromocriptine is a glutamate transporter activator as well as a D2
dopamine receptor agonist (Yamashita et al., 1995, 1998).
GLAST deficiency led to a slightly increased level of the basal
glutamate in perilymph before noise exposure and the slight (~10 dB)
ABR threshold elevations in untreated mutant mice. However, no obvious
abnormality at hair cell or dendrite levels could be observed before
noise exposure in mutant mice. Previous studies show that, when hearing
losses after noise trauma are not >40 dB, only light mechanical and/or
electrical dysfunction occurs (Puel et al., 1998). Thus it is likely
that the increased glutamate level in untreated mutant mice is
sufficient to elevate the ABR threshold, but insufficient to produce
structural damage, although we cannot rule out a possibility that some
other yet undetected defect in mutant mice leads to the baseline ABR
threshold elevation. In the present study, we could not detect
increased amounts of glutamate in noise-stimulated perilymphs in the
wild-type mice, consistent with previous studies (Eybalin,
1993). However, we succeeded in demonstrating an increase of the
perilymphatic concentration of glutamate during and after sound
stimulations in GLAST-deficient mice. These results indicate that GLAST
is a powerful glutamate uptake system in the cochlea and that GLAST
hampers the reliable detection of increased amounts of glutamate in
noise-stimulated perilymphs by previous works. Our data also provide
direct evidence for the hypothesis that glutamate is a neurotransmitter
of synapses between IHC and the auditory nerve. In our data, there are
two discrepancies between glutamate levels and the effects of glutamate on the ABR thresholds (Figs. 2, 3). First, GLAST mutant mice show a
partial recovery of the ABR threshold, whereas glutamate levels in
perilymphs remain high even at 120 min after sound exposure. The
mechanism of such discrepancy is unknown, but a reasonable explanation
is that a decrease of the cochlea blood flow and damage to hair-cell
stereocilia induced by acoustic overstimulation could recover within
120 min after sound exposure. Further work will be required to unravel
the detailed mechanisms of recovery. Second, noise causes an ABR
threshold elevation but no glutamate rise in the wild-type mice. This
discrepancy can be explained by the inherent problem in a microdialysis
approach. Because a microdialysis technique cannot directly measure the
concentration of glutamate in the synaptic cleft but monitors the
concentration of glutamate that diffuses out of the synaptic cleft into
perilymph, and because the wild-type mice have a powerful glutamate
uptake system (GLAST) in the cochlea, we cannot detect an increase of
the perilymphatic concentrations of glutamate during and after sound
stimulation in the wild-type mice, although the concentration of
glutamate in the synaptic cleft really increases.
GLAST mutant mice will provide a model system for the investigation of
the contribution of excitotoxic mechanisms to various cochlear diseases.
| |
FOOTNOTES |
Received June 19, 2000; revised Sept. 18, 2000; accepted Sept. 20, 2000.
This work was supported in part by research grants from the Ministry of
Education, Science, and Culture of Japan, the Ministry of Health and
Welfare of Japan, Uehara Memorial Foundation, Brain Science Foundation,
Yamada Science Foundation, Toyota Physical and Chemical Research
Institute, The Karoji Memorial Fund, and the Japan Spina Bifida and
Hydrocephalus Research Foundation. We thank Yutaka Takumi, Naoya
Iijima, and Katsuhiko Kobatashi for their help with immunocytochemical techniques.
Correspondence should be addressed to Kohichi Tanaka, Department of
Molecular Neuroscience, Medical Research Institute, Tokyo Medical and
Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
E-mail: tanaka.aud{at}mri.tmd.ac.jp.
| |
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ABSTRACT
INTRODUCTION
