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Department of Physiology and Biophysics, School of Medicine, University of Washington, Seattle, Washington 98195-7290
Submitted 7 February 2003; accepted in final form 4 April 2003
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ABSTRACT |
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INTRODUCTION |
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).
This effect is at least partially mediated by ethanol's actions on
ligand-gated channels to depress overall synaptic activity in the nervous
system. Ethanol is generally thought to inhibit excitatory transmission and
increase inhibitory transmission via its modulation of neurotransmitter
receptor-mediated currents (Crews et al.
1996). Inhibitory synaptic transmission is mediated by two
neurotransmitters, GABA and glycine. Currents mediated by both GABA and
glycine neurotransmitter receptors are modulated by ethanol. Ethanol typically
potentiates glycine-activated currents in cultured cells as shown by studies
in mouse hippocampal and cortical neurons
(Aguayo and Pancetti 1994),
mouse spinal cord motoneurons (Aguayo et
al. 1996), and Xenopus oocytes
(Mascia et al. 1996), although
ethanol has also been shown to inhibit glycinergic current in some cultured
rat ventral tegmental neurons (Ye et al.
2001). Ethanol's effects on GABAergic currents are
characteristically variable and depend on many factors including cell type,
dose of ethanol, and method of ethanol application. In cultured and
dissociated rat neurons, extracted from a variety of brain regions, and rat
brain slices, GABA-activated currents were potentiated by low concentrations
of ethanol in a cell type specific manner
(Nishio and Narahashi 1990;
Proctor et al. 1992). Ethanol
(1–50 mM) increased the current to a greater degree and in a larger
percentage of sampled cells in cerebral cortex compared with the cerebellum
(Reynolds et al. 1992).
Ethanol-mediated potentiation of GABAergic currents recorded from chick spinal
cord neurons was protocol dependent, while the potentiation of glycinergic
currents was more robust and consistent
(Celentano et al. 1988).
Studies from our laboratory have shown that ethanol potentiates currents
mediated by native glycine receptors in hypoglossal motoneurons (HMs) in a
developmentally dependent manner (Eggers
et al. 2000). The effects of ethanol on GABAA receptor
(GABAAR)-mediated synaptic currents are of interest as well,
because GABA and glycine are co-released onto HMs
(O'Brien and Berger 1999) and
spinal cord motoneurons (Jonas et al.
1998) and therefore jointly determine the extent of inhibition to
these neurons. Therefore we examined the effect of ethanol on miniature
inhibitory postsynaptic currents (mIPSCs) mediated by native
GABAARs and compared these data to the ethanol-induced potentiation
of glycinergic mIPSCs. |
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METHODS |
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).
Whole cell patch-clamp recordings were performed at room temperature using
2–4M
resistance patch electrodes. The electrodes were filled with
(in mM) 140 CsCl, 2 MgCl2, 10 HEPES, 10 EGTA, 2 ATP, and 0.2 GTP
(pH 7.2). HMs were voltage clamped at –55 to –60 mV. The bath
solution contained 6,7-dinitro-quinoxaline (DNQX, RBI),
D(–)-2-amino-5-phosphonopentanoic acid (APV, Tocris), TTX
(Alomone Labs), and bicuculline methiodide (BMI, Sigma) or strychnine
hydrochloride (Sigma). In some experiments in which glycinergic mIPSCs were
recorded CdCl2 (100 µM) was also added to the bath solution. The
series resistance was measured after each recording period and the data were
discarded if the resistance changed by more than 25% or if the series
resistance was >10 M. Data were acquired at 5 kHz using Clampex
software (Axon Instruments) and filtered at 2 kHz. Representative raw traces
were additionally filtered at 1 kHz in Clampfit (Axon Instruments).
Spontaneous mIPSCs were analyzed using software developed in our laboratory
and MiniAnalysis software (Synaptosoft). For all cells, the decay of the
average mIPSC was fit to one or two exponentials. A weighted decay time
constant, 
decay, was calculated for all traces fit by two
exponentials using the time constants and the relative amplitudes:
decay = (1a1 +
2a2)/(a1 +
a2). A paired t-test was used to compare
differences in mean values for different conditions. Data are reported as mean
± SE. Kolmogorov-Smirnov (K-S) test was used to assess differences in
mIPSC histogram distributions.
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RESULTS |
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).
Glycinergic currents from juvenile HMs are more sensitive to ethanol than
glycinergic currents from neonate HMs and this increase in ethanol sensitivity
observed with postnatal development correlates with both a shortened decay and
a subunit shift from the 
2 to 1 glycine
receptor subunit. GABAergic mIPSC decay duration decreases with postnatal development, but amplitude and frequency do not change
We compared the amplitude, frequency, and decay of GABAergic mIPSCs
recorded in control conditions for neonate and juvenile HMs
(Table 1). We found that the
amplitude and frequency of mIPSCs between the two age groups were not
significantly different. In contrast, the weighted decay time constant
significantly decreased from neonate to juvenile ages. In previous studies,
our laboratory has reported similar mean GABAergic mIPSC amplitudes in HMs
(O'Brien and Berger 1999,
2001). Also, the reduction in
the GABAergic mIPSC decay with postnatal development is consistent with our
laboratory's previous results (O'Brien and Berger
1999,
2001).
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Bath application of 30 mM ethanol had no effect on GABAergic mIPSC frequency, amplitude, and decay
Bath application of 30 mM ethanol did not change the frequency, amplitude,
or decay of GABAergic mIPSCs recorded from neonate and juvenile HMs.
Representative raw traces in Fig. 1,
A1, A2 and B1, B2 show that the frequency of
GABAergic mIPSCs did not change following ethanol application. For the overall
population of HMs tested, the average frequency of mIPSCs did not
significantly change following ethanol application at neonate (1.7 ±
1.1 to 2.2 ± 1.3 Hz, n = 5, P > 0.1, paired
t-test) and juvenile (1.1 ± 0.7 to 1.1 ± 0.9 Hz,
n = 5, P > 0.7, paired t-test) ages. The average
weighted decay measured from the same GABAergic mIPSCs did not
change following ethanol application at neonate (47 ± 9 to 45 ±
7 ms, n = 5, P > 0.6, paired t-test) and
juvenile (41 ± 8 to 40 ± 4 ms, n = 5, P >
0.9, paired t-test) ages. The average traces, each from more than 100
mIPSCs recorded from two HMs, are shown in
Fig. 1, A3 and
B3, and show no change in either peak amplitude or decay
in the presence of ethanol. The average amplitudes of GABAergic mIPSCs
recorded from HMs were unaffected by ethanol application at neonate (43
± 4 to 39 ± 2 pA, n = 5, P > 0.3, paired
t-test) and juvenile (38 ± 3 and 35 ± 1 pA, n
= 5, P > 0.3, paired t-test) ages.
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Bath application of 100 mM ethanol increased the frequency, but decreased the amplitude of GABAergic mIPSCs in a developmentally dependent manner
Representative raw traces in Fig.
2 reflect an increased mIPSC frequency for both age groups
following 100 mM ethanol application. The frequency histogram distributions of
GABAergic mIPSCs amplitudes recorded from the cells in
Fig. 2, A1, A2 and B1,
B2, are shown in Fig. 2,
A3 and B3. The distribution of mIPSC amplitudes
from juvenile HMs shows a leftward shift toward smaller peak amplitudes
following ethanol application that is not apparent in the neonate recordings.
The mIPSC amplitude distributions for seven of eight cells tested are
significantly different between control and ethanol for juvenile HMs (K-S,
n = 7, P < 0.05), but the amplitude distributions for
neonate HMs were not significantly different (K-S, n = 12, P
> 0.9). The average GABAergic mIPSC amplitudes recorded from neonate HMs
(n = 12) in the control condition slightly but significantly
decreased following 100 mM ethanol application by 6 ± 3% (paired
t-test, P < 0.05), from 36 ± 3 to 33 ± 2
pA. Ethanol application significantly decreased the average amplitudes
recorded from juvenile HMs (n = 8) by 16 ± 3% (paired
t-test, P < 0.01) from 42 ± 4 pA, in the control
condition, to 33 ± 3 pA with ethanol. The average traces
(insets) are consistent with this finding in that the mIPSC peak
amplitude recorded from a neonate decreases only slightly in the presence of
100 mM ethanol, but the average mIPSC peak amplitude recorded from the older
animal decreased to a larger extent when 100 mM ethanol was applied. The
average mIPSC frequency recorded from neonate HMs (n = 12) increased
by 64 ± 17% (1.7 ± 0.3 to 2.8 ± 0.6 Hz, paired
t-test, P < 0.01). The frequency histogram distribution
of inter-event intervals for the juvenile HM
(Fig. 2B4) shows a
decrease in interval following ethanol application. However, the frequency of
GABAergic mIPSCs recorded from all juvenile HMs studied did not increase
significantly (1.5 ± 0.3 to 2.0 ± 0.5 Hz, n = 8, paired
t-test, P < 0.2). The average weighted
decay did not change following ethanol application at neonate (56
± 5 to 58 ± 8 ms, n = 5, P > 0.7, paired
t-test) and juvenile (41 ± 6 to 41 ± 6 ms, n =
5, P > 0.8, paired t-test) ages.
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The effects of 30 and 100 mM ethanol on GABAergic mIPSC amplitude, frequency, and decay are summarized and presented as a percentage of change from control values in Fig. 3. We see that the amplitude and frequency were modulated by ethanol in a dose- and developmentally dependent manner, although the decay time was unaffected. The amplitude of GABAergic mIPSCs recorded from older rats decreased more following 100 mM ethanol bath application than were mIPSCs recorded from neonates. The frequency of GABAergic mIPSCs significantly increased only at the higher ethanol concentration in neonate HMs. The observation common among the data sets is the large variability of ethanol's effects.
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Ethanol at 100 mM differentially affected GABAergic and glycinergic mIPSCs
We next compared our results on GABAergic mIPSCs with the effects of 100 mM
ethanol on glycinergic mIPSCs. Responses of glycinergic mIPSCs recorded in
this study support our previously published data
(Eggers et al. 2000) that
demonstrated ethanol (100 mM) potentiated mIPSC amplitude and increased mIPSC
frequency. We pooled our previously published data (n = 18,
Eggers et al. 2000) with
additional data from glycinergic mIPSCs (n = 8) and compared all
these responses to those of GABAergic mIPSCs. Ethanol at 100 mM potentiated
glycinergic mIPSC peak amplitude by 31 ± 3 and 41 ± 7%, in
neonates and juveniles, respectively. In contrast, ethanol decreased the
amplitude of GABAergic mIPSC peak amplitude by 6 ± 3 and 16 ± 3%
in neonates and juveniles, respectively. Although ethanol modulated GABAergic
and glycinergic mIPSC peak amplitudes in opposite directions, it increased the
frequency of both types of mIPSCs (Fig.
4). The frequency of GABAergic mIPSCs only significantly increased
at the younger age, but the frequency of glycinergic mIPSCs increased to a
much greater degree at both ages. Ethanol elicited more robust effects on
glycinergic mIPSC amplitude and frequency, suggesting that glycinergic
transmission is more sensitive to ethanol modulation than GABAergic
transmission.
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DISCUSSION |
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Developmental dependence of ethanol's actions
The glycine receptor (GlyR) undergoes a subunit switch during postnatal
development, from the 2 to 1 subunit, that
correlates with a shortened glycinergic mIPSC decay
(Singer et al. 1998). This
subunit switch is likely to explain the more robust ethanol-mediated
potentiation of glycinergic currents recorded from juvenile HMs
(Eggers et al. 2000;
Mascia et al. 1996). The
weighted decay of GABAergic mIPSCs in the present study also
shortened over postnatal development. The present study demonstrates an
interesting parallel between glycinergic mIPSCs and GABAergic mIPSCs recorded
in neonate and juvenile HMs. GABAergic mIPSC decay shortened during postnatal
development and GABAergic mIPSCs recorded in juvenile HMs were more sensitive
to ethanol modulation than those recorded in neonate HMs. The shortened decay
accompanied by an increased sensitivity to ethanol suggest that a subunit
shift in the GABAAR occurs during development. Immunohistochemical
studies have shown that neonatal HMs express the GABAAR
2 subunit but not the 1 subunit
(Donato and Nistri 2000). A
recent study has shown that GABAAR 1 subunit
staining is weak in neonatal HMs, but is stronger in juvenile HMs
(O'Brien and Berger 2001). In
adult HMs, the 1, 2, and
2 subunits are the predominant GABAAR subunits
expressed (Fritschy and Mohler
1995). It is therefore possible that 2 subunit
expression is favored in neonatal HMs followed by an increase in
1 subunit expression during development. Ethanol's brain
region specific effects suggest that some subunits or subunit combinations
render GABAARs more readily modulated by ethanol
(Blednov et al. 2003;
Reynolds et al. 1992;
Ueno et al. 1999). A
GABAAR subunit composition change in HMs during postnatal
development might explain the greater degree of ethanol-mediated inhibition in
older HMs.
Variability of ethanol's effect on GABAergic currents
Most electrophysiological studies have shown that ethanol increases
GABAergic currents (Aguayo
1990; Reynolds et al.
1992; Wafford et al.
1991; Weiner et al.
1994). However, this is not a wholly consistent result. One
characteristic of ethanol's action on GABAergic currents is that the effects
vary depending on GABAAR subunit composition expressed, preparation
used, concentration of ethanol, brain region, and age of animals. Wafford et
al. reported that low concentrations of ethanol increased currents mediated by
GABAARs expressed in Xenopus oocytes, and that the
2L subunit was required for potentiation (Wafford et al.
1990,
1991). Subsequent studies
investigated this proposal that the 2L subunit is required
for ethanol-mediated potentiation (reviewed by
Mihic 1999). These studies
showed that GABAergic currents recorded from Xenopus oocytes
(Harris et al. 1997) and
dorsal root ganglion (Zhai et al.
1998) cells expressing the 2L subunit were not
potentiated at low doses (<100 mM). In another study, GABAergic currents
recorded from Xenopus oocytes expressing
1
12S,
112L, and
122S GABAARs
were potentiated only at higher ethanol concentrations (>60 mM)
(Sigel et al. 1993). Ethanol
had no differential effect on currents mediated by receptors containing the
2S versus the 2L subunit. Further, a lower
dose of ethanol (50 mM) potentiated GABA-activated currents mediated by
heteromeric GABAARs
(212L) expressed in
Xenopus oocytes. The potentiation was more dependent on the
expression of the 2 and 1 than the
2L subunit (Ueno et al.
1999). Thus in the Xenopus oocyte expression system, the
sensitivity of GABAARs to ethanol modulation depends not on the
presence of the 2L subunit but on the combination of
subunits expressed. The effect of ethanol on GABAergic currents recorded from
chick-, mouse-, and rat-cultured neurons is highly concentration dependent and
cell type specific. Low concentrations of ethanol (
50 mM) potentiate
GABA-activated currents recorded from neurons in the mouse hippocampus, chick
cortex, and spinal cord and rat cortex and cerebellum
(Reynolds et al. 1992).
GABAergic currents recorded from cultured rat dorsal root ganglions neurons
(White et al. 1990), however,
were insensitive to ethanol at concentrations 100 mM, while GABAergic
currents recorded from superior cervical ganglion neurons were inhibited by
the same range of ethanol concentrations
(Aguayo and Alarcon 1993). In
the same study, Aguayo et al. also showed that ethanol at concentrations
100 mM inhibited GABAergic currents recorded from adult SCG cells more
than currents recorded from newborn SCG cells. The effect of ethanol on
GABAergic currents recorded from slice preparations is no more consistent.
GABAergic currents recorded from rat brain slices dissected from different
regions have shown that ethanol potentiates evoked IPSCs in the cortex, and
the intermediate and medial septal nuclei, but has no effect on the
hippocampus (Soldo et al.
1994). In spinal cord slices, bath application of 70 mM ethanol
significantly increased the frequency of GABAergic spontaneous inhibitory
postsynaptic currents (Cheng et al.
1999) and mIPSCs
(Ziskind-Conhaim et al. 2003)
recorded from postnatal rat spinal cord motoneurons, but not the amplitude.
Although ethanol generally increases GABAergic currents, ethanol potentiates
glycinergic currents much more consistently across experimental preparations.
A possible explanation for the variability on ethanol's effects of GABAergic
currents is the great diversity of GABAAR subunits and receptor
compositions.
GABAARs are heteromeric complexes composed of five subunits of
which the major classes are , , , 
, 
, 
,
and 
(Crews et al. 1996;
Whiting et al. 1999). Each of
the subunit classes consists of multiple isoforms that are further diversified
by posttranslational processing. GlyRs can be homomeric and heteromeric
complexes composed of four receptor subunits, 1,
2, 3, and , that can also be further
diversified by alternative splicing and posttranslational processing
(Crews et al. 1996). Although
the 1 GlyR subunit is thought to confer greater ethanol
sensitivity (Mascia et al.
1996), it is still controversial which GABAAR subunits
or subunit combinations are most readily modulated by ethanol
(Ueno et al. 1999;
Wafford et al. 1991).
GABAARs that are sensitive to ethanol modulation may be localized
in a few brain regions and each region may express multiple types of
receptors. In this way, the diversity of GABAARs may account for
the variability of effects ethanol has on GABAergic currents.
Differential effects on presynaptic and postsynaptic transmission
At 100 mM, ethanol significantly increased the GABAergic mIPSC frequency in
neonate, but not in juvenile HMs. The frequency of mIPSCs is controlled by
presynaptic mechanisms that determine the synaptic vesicle release
probability. Although the mechanisms involved in ethanol's actions on
neurotransmitter release are unknown, it is possible that ethanol increases
the release probability of synaptic vesicles containing inhibitory
neurotransmitters by modulating the presynaptic Ca2+
concentration. Ethanol has a concentration-dependent effect on
muscarine-stimulated norepinephrine (NE) release from PC12 cells that
correlate with changes in intracellular Ca2+
concentrations (Rabe and Weight
1988). At the physiological concentration of ethanol tested (100
mM), ethanol inhibits muscarine-stimulated NE release and the increase of
intracellular-free Ca2+. Ethanol also inhibits
voltage-gated channels, particularly L-type channels, in PC12 cells and intact
brain (Crews et al. 1996).
Releasing Ca2+ from intracellular stores stimulates
spontaneous neurotransmitter release
(Emptage et al. 2001). Ethanol
may act on voltage-gated Ca2+ channels or intracellular
Ca2+ stores to change the presynaptic
Ca2+ concentration and modulate synaptic vesicle release
probability.
In addition to its effects on GABAergic mIPSCs recorded from neonate HMs, 100 mM ethanol also induced an average increase in the frequency of GABAergic mIPSCs recorded from juvenile HMs. However, this effect was not statistically significant. It is possible that the release machinery in neurons innervating the HMs of the juvenile rat is not as sensitive to ethanol modulation as in the neonatal rat. Alternatively, a significant increase in average mIPSC frequency at juvenile ages may have gone undetected because ethanol decreased the mIPSC peak amplitudes to a value below the detection threshold.
Although both pre- and postsynaptic mechanisms can determine the peak mIPSC
amplitude, conventionally mIPSC amplitude changes are thought to reflect
changes in the response of postsynaptic receptors
(Thompson et al. 1993).
Ethanol is thought to potentiate the amplitude of glycinergic currents by
acting on postsynaptic GlyRs. A single amino acid on the GlyR
1 subunit confers greater ethanol sensitivity when homomeric
GlyR are expressed in Xenopus oocytes
(Mascia et al. 1996). An
analogous site for ethanol's actions on the GABAAR has not been
found. Instead, as discussed above, it is thought that the combination of
receptor subunits expressed determines ethanol sensitivity. The opposing
effects ethanol has on frequency and amplitude suggest that ethanol modulates
GABAergic synaptic transmission differently presynaptically versus
postsynaptically.
Physiological effects of ethanol modulation
The reliability of ethanol's potentiation of glycinergic currents and the
variability of its effects on GABAergic currents suggest that ethanol
modulates inhibitory synaptic transmission in the hypoglossal nucleus
primarily by acting on glycine receptors. HMs innervate the tongue muscle,
which plays a role in regulating airway patency. Inhibition of HMs partially
contributes to obstructive sleep apnea (OSA)
(Yamuy et al. 1999), which
occurs when the tongue collapses into the airway
(Remmers et al. 1980). During
a pharmacologically induced model of REM sleep, a sleep state when OSA is
generally most prevalent, HMs receive large glycinergic IPSPs. Administering
ethanol to humans suffering from OSA intensifies the severity of sleep apnea
by increasing the duration and frequency of apneic events and decreasing the
arterial oxygen saturation (Issa and
Sullivan 1982; Scrima et al.
1982; Taasan et al.
1981). Ethanol consumption not only intensifies sleep apnea in
patients suffering from OSA, it also induces apneic events in chronic snorers
(Issa and Sullivan 1982).
Ethanol may exacerbate OSA in part by increasing inhibition by potentiating
glycinergic currents. Although ethanol had opposing effects on pre- and
postsynaptic transmission by potentiating and inhibiting GABAergic currents,
the effect was generally weaker than the response of glycinergic currents.
Therefore GABAergic currents may not significantly contribute to the
heightened inhibition of HMs during OSA, particularly following ethanol
consumption.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests: J. Y. Sebe, Department of Physiology and Biophysics, School of Medicine, University of Washington, Box 357290, Seattle, WA 98195-7290 (E-mail: sebe{at}u.washington.edu).
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