Group Title: Molecular Pain 2006, 2:36
Title: Relationship between tonic inhibitory currents and phasic inhibitory activity in the spinal cord lamina II region of adult mice
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Title: Relationship between tonic inhibitory currents and phasic inhibitory activity in the spinal cord lamina II region of adult mice
Series Title: Molecular Pain 2006, 2:36
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Creator: Ataka T
Gu JG
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Short report W

Relationship between tonic inhibitory currents and phasic inhibitory
activity in the spinal cord lamina II region of adult mice
Toyofumi Ataka1,2 and Jianguo G Gu*


Address: 'Department of Oral and Maxillofacial Surgery, McKnight Brain Institute and College of Dentistry, University of Florida, Gainesville,
Florida 32610, USA and 2Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
Email: Toyofumi Ataka ata-p@med.niigata-u.ac.jp; Jianguo G Gu* jgu@dental.ufl.edu
* Corresponding author


Published: 27 November 2006
Molecular Pain 2006, 2:36 doi:10.1 186/1744-8069-2-36


Received: 01 November 2006
Accepted: 27 November 2006


This article is available from: http://www.molecularpain.com/content/2/1/36
2006 Ataka and Gu; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Phasic and tonic inhibitions are two types of inhibitory activities involved in inhibitory processing
in the CNS. In the spinal cord dorsal horn, phasic inhibition is mediated by both GABAergic and
glycinergic inhibitory postsynaptic currents. In contrast to phasic inhibitory currents, using patch-
clamp recording technique on spinal cord slices prepared from adult mice we revealed that tonic
inhibitory currents were mediated by GABAA receptors but not by glycine receptors in dorsal horn
lamina II region. We found that there was a linear relationship (r = 0.85) between the amplitude of
tonic inhibitory currents and the frequency of GABAergic inhibitory postsynaptic currents. Analysis
of charge transfer showed that the charges carried by tonic inhibitory currents were about 6 times
of charges carried by phasic inhibitory currents. The prominent charge transfer by tonic inhibitory
currents and their synaptic activity dependency suggest a significant role of tonic inhibition in
sensory processing.


Background
GABA (y-Aminobutyric acid) and glycine are two princi-
ple inhibitory neurotransmitters in the spinal cord dorsal
horn. They are either released separately or co-released
from presynaptic terminals of inhibitory neurons. Upon
the binding to GABAA receptors and glycine receptors at
postsynaptic membrane, they elicit inhibitory postsynap-
tic currents (IPSCs). IPSCs provide phasic inhibition in
neuronal network and are important for information
processing. In addition to its action at synaptic sites,
recent studies in several brain regions of matured animals
have indicated that low concentrations of ambient GABA
can activate high affinity GABAA receptors that are
expressed at extrasynaptic sites to elicit a sustained inhib-
itory current [1-5]. A term 'tonic inhibitory currents' has
been used to describe this sustained inhibitory current [6].
Functionally, tonic GABAergic inhibition has been shown


to control neuronal excitability in the brain [7-9]. Tonic
inhibitory currents have been identified in rat cerebellar
granule cells [ ], granule cells of the dentate gyms [2], tha-
lamocortical relay neurons of the ventral basal complex
[3], layer V pyramidal neurons in the somatosensory cor-
tex [4], inhibitory intemeurons in the CA1 region of the
hippocampus [5]. However, not all CNS neurons that
were examined displayed tonic inhibitory currents under
normal conditions. For example tonic inhibitory currents
were normally not observed in hippocampal pyramidal
cells in brain slices from adult animals [[5,10], but see
[11]].

The lamina II of the spinal dorsal horn substantiala gelati-
nosa) plays an important role in processing nociceptive
input from fine myelinated A6 and unmyelinated C-pri-
mary afferents from the periphery [12]. In this area, inhib-


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itory neurons produce feedback and feed-forward
inhibition to control nociceptive input, and a reduction of
inhibitory activity in lamina II can result in central sensi-
tization [13,14]. Previous studies on inhibitory controls
in the spinal cord dorsal horn have been mainly focused
on inhibitory postsynaptic currents, i.e. phasic inhibition.
Little is known about whether tonic inhibitory currents
are present in this region and if so, whether tonic inhibi-
tory currents are mediated by GABA receptors and/or gly-
cine receptors.

Materials and methods
The methods for preparing thick adult mouse spinal cord
slices, as well as blind whole-cell patch-clamp recording
techniques, have been described previously [15]. In brief,
transverse spinal cord slices (500-600 gm in thickness)
were prepared from L5 spinal cords of adult mice (Harlan,
IN, USA) aged between 6 and 9 weeks. In each experi-
ment, a spinal cord slice was transferred to a recording
chamber (volume of 0.5 ml). The slice was supported at
the bottom by a nylon mesh in the recording chamber.
The slice was superfused with Krebs solution at flow rate
of 10 ml/min. The Krebs solution contained (in mM):
NaCl 117, KC1 3.6, CaCl2 2.5, MgC12, 1.2, NaH2PO4 1.2,
NaHCO3 25, and glucose 11. The solution was equili-
brated with 95% 02 and 5% CO2, maintained at room
temperature (22 C), and the pH of the Krebs solution was
7.35. Under a dissecting microscope with 40x magnifica-
tion, lamina regions were identified based on morpholog-
ical features. The lamina II was clearly discernible as a
relatively translucent band across the superficial dorsal
horn. Under visual guidance, the patch electrode was
inserted vertically into the lamina II.

Whole-cell patch-clamp recordings were made from lam-
ina II neurons with electrodes (5~10 MQ) filled with an
internal solution containing (in mM): K-gluconate 120,
KC1 20, MgCl2 2, Na2ATP 2, NaGTP 0.5, HEPES 20, EGTA
0.5, and pH 7.2 adjusted with NaOH. Signals were ampli-
fied and filtered at 2 kHz and sampled at 5 kHz (Axopatch
200B). Spontaneous inhibitory postsynaptic currents
(sIPSCs) were recorded with cells being held at 0 mV. Each
recording was performed on a cell in a fresh slice without
prior application of any agonist or antagonist. Isolation of
GABAergic sIPACs was accomplished by including 2 igM
strychnine in the bath solution. Tonic inhibitory currents
were revealed following the application of 20 gM bicucul-
line for a period of 3 min. All compounds tested were
applied through the bath solution at a flow rate of 10 ml/
min. Analysis of sIPSCs, including threshold setting and
peak identification criteria, were performed according to a
method previously described [15]. Decay time constant
(z) of sISPCs was analyzed using Clampfit 9 (Axon Instru-
ments, Inc., Sunnyvale, CA, USA). sIPSC frequency,
amplitude, and average charge transfer (Qslescs, integrated


area under sIPSCs) were analyzed using Mini Analysis
Program (Synaptosft, Inc., Decatur, GA, USA). Charge
transfer (Qpc) associated with sIPSCs in a given time (t)
was calculated using the equation Qpc = f x Qsescs x t,
where f is the frequencies (Hz) of sIPSCs, Qs1scs is the
average charge transfer per sIPSC during a 60-s baseline
recording, and t is the duration (60 s), respectively. The
charge transfer associated with tonic currents was calcu-
lated according to the equation: QTc = ITc x t, where QTc is
the charge transfer produced by tonic currents, ITc is the
current amplitude at steady-state, and t is time (60 s).
Unless otherwise indicated, data represent Mean SEM,
Student's t-tests were used for statistical comparison, and
significance was considered at the P < 0.05 level.

Results
Under our voltage-clamp condition with cells being held
at 0 mV, spontaneous inhibitory postsynaptic currents
(sIPSCs) recorded from lamina II neurons were outward
currents, and spontaneous excitatory postsynaptic cur-
rents (sEPSCs) were not detectable because the holding
potential of 0 mV is at the reversal potential for sEPSCs.
Phasic inhibitory activities (or sIPSCs) showed three
types, rapid, slow, and mixed types, based on the kinetics
of their decay phases. When these different types of sIPSCs
are integrated together, it yields an sIPSC that best fits into
a two-exponential equation (Figure 1A). Following the
application of 2 iM strychnine to block glycine receptors,
rapid type of sIPSCs disappeared but slow sIPSCs
remained. When bath solution contained 20 iM bicucul-
line but not strychnine, only rapid type of sIPSCs could be
observed (Figure 1A). All sIPSCs could be completely
blocked in the presence of both bicuculline (2 iM) and
strychnine (20 iM, not shown).

Application of 20 iM bicuculline not only inhibited slow
types of sIPSCs, but also caused a shift of baseline holding
current (Figure 1B). The shift of baseline hold currents
represents the presence of tonic inhibitory currents medi-
ated by GABAA receptors [6]. The amplitudes of the tonic
inhibitory currents revealed by bicuculline were 8.4 + 0.7
pA (n = 30, Figure ID). After washing off bicuculline, hold
currents returned to the baseline levels.

Glycinergic inhibitory postsynaptic currents contributed
to phasic inhibitory activity in lamina II region, and appli-
cation of glycine receptor antagonist strychnine (2 iM)
blocked glycinergic sIPSCs. However, there was no signif-
icant change of baseline holding currents following the
application 2 gM strychnine (Figure 1C). The baseline
holding currents were -0.3 0.5 pA (n = 6) in lamina II,
not significantly different from the baseline noise level
(Figure 1D). These results suggested that glycine receptors
did not significantly account for the tonic inhibitory cur-
rents in dorsal horn lamina II neurons of adult mice.


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Control




4_50 pA
Stry 250 ms




50 pA
250 m s
Bic .. .. .




-750 pA
250 m s


rT = 6.5 ms
2 = 38 ms 8 pA
3 10 1ms




T=33ms 8 pA
10 ms





S=6.5ms 8 pA

10 ms


strychnine (2 pM)


10 *
10






Q2


Bicuculline Strychnine

Figure I
Revealing tonic inhibitory currents in lamina II neurons of adult mice. A). Traces on the left side show slPSCs
recorded in normal bath solution (control), following the applications of either 2 pM strychnine (Stry) or 20 pM bicuculline
(Bic). Traces on the right side are the average of 100 slPSCs. z is time constant for averaged trace. B). Sample trace (top panel)
shows the shift of baseline holding current following the application of 20 pM bicuculline. The lower traces show at an
expanded scale the baselines before and during bicuculline application as well after wash off bicuculline. C). Sample trace shows
that application of strychnine (2 pM) inhibited some slSPCs but did not affect baseline holding current. D). Bar graph shows
pooled results of baseline shift following the application of either 20 pM bicuculline (n = 30) or 2 pM strychnine (n = 6). Bicuc-
ulline or strychnine was applied for 3 min in each experiment.





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Amplitude of tonic inhibitory currents showed large vari-
ations among different recordings. One possible cause of
this variation might be due to the differences of resting
membrane potentials of these neurons. Therefore, we
measured resting membrane potentials of each recorded
neurons and plotted amplitudes of tonic inhibitory cur-
rents against resting membrane potentials of each record-
ing. No relationship was found between tonic inhibitory
current amplitudes and resting membrane potentials (r =
0.27, n = 30, Figure 2A). We determined whether ampli-
tude of tonic inhibitory currents were in proportional to
inhibitory synaptic inputs by plotting tonic inhibitory
current amplitude against sIPSC frequency. We also did
not find a strong association between the amplitudes of
tonic inhibitory currents and the frequency of total sIPSCs
(r = 0.5, n = 30, Figure 2B).

Total sIPSCs in the spinal cord dorsal horn included both
glycinergic and GABAergic inhibitory synaptic activity. We
isolated GABAA receptor-mediated sIPSCs from total sIP-
SCs by including 2 ipM strychnine in bath solution. Under
this condition, glycine receptor-medicated sIPSCs were
completely abolished. We then applied 20 ipM bicuculline
to reveal tonic currents, and we found that neurons receiv-
ing higher frequency of GABAergic synaptic inputs usually
had larger amplitudes of tonic inhibitory currents (Figure
3A), and neurons receiving lower frequency of GABAergic
synaptic inputs usually had smaller amplitudes of tonic
inhibitory currents (Figure 3B). There was a good linear
relationship between the amplitude of GABAergic tonic
inhibitory currents and the frequency of GABAergic IPSCs
(r = 0.8515, n = 14, Figure 3C).

Charge transfer through GABAA receptors is a measure of
inhibition for both phasic and tonic inhibitory currents.
We determined charge transfer carried by phasic inhibi-
tory currents and by tonic inhibitory currents in a period
of 60 sec recording (Figure 4A). Charge transfer was 1.5 +
0.31 pC (n = 44) for the total phasic currents mediated by
both GABAergic and glycinergic inhibitory postsynaptic
currents (Figure 4B). On the other hand, charge transfer
was 8.7 + 0.89 pC (n = 44) for tonic inhibitory currents
mediated by GABAA receptors, and was about 6 times of
the total charge transfer mediated by both GABAergic and
glycinergic inhibitory postsynaptic currents (Figure 4B).

Discussion
Using spinal cord slice preparations from adult mice, the
present study shows that tonic inhibitory currents are
present in lamina II of the dorsal horn and was solely
mediated by GABAA receptors, that the extent of tonic
inhibition is proportional to GABAergic inhibitory synap-
tic activity, and that tonic currents transfer charges sub-
stantially higher than phasic currents. The results provide


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Figure 2
Lack of correlation between tonic inhibitory currents
and resting membrane potentials as well as between
tonic inhibitory currents and total slPSC activity. A).
Graph shows a plot of tonic inhibitory currents against mem-
brane potentials for each recorded neuron (n = 30). B).
Graph shows a plot of tonic inhibitory current against slPSC
frequency (n = 30). Tonic inhibitory currents were revealed
by the applications of 20 piM bicuculline. Both resting mem-
brane potentials and slPSCs were measured before the appli-
cation of bicuculline.


new information about inhibitory activities in a nocicep-
tive processing region.

We have observed a large variation of the size of tonic
inhibitory currents. It has been suggested that ambient
GABA concentrations around the extrasynaptic domains
of neurons is a factor that determines the size of tonic
inhibitory currents. The concentrations of ambient GABA


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Molecular Pain 2006, 2:36


1








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Qpc = QsPsc x F x At


QTC = TX At


Bicuculline
Sstrychnine



Y~--L~h"*I ~-


1 20 pW
10s

I 20 pA
200 ms


B






go
so

3s


r = 0.8515


0 5 10 15 20 25 30 35
GABAergic slPSC frequency (Hz)

Figure 3
Correlation between tonic inhibitory currents and
GABAergic inhibitory synaptic activity. A). Sample
trace shows bicuculline-induced baseline shift in a lamina II
neuron with high GABAergic inhibitory synaptic activity. B).
Sample trace shows bicuculline-induced baseline shift in
another lamina II neuron with low GABAergic inhibitory syn-
aptic activity. C). Plot of GABAergic tonic inhibitory currents
against frequency of GABAergic slPSCs (n = 14). Linear
regress coefficient (r) = 0.85 15. All experiments were per-
formed in the presence of 2 pM strychnine.



vary from tens of nanomolar to a few micromolar based
on in vivo microdialysis studies in the brain [16-19]. One
possible cause of the variation may be regional and tem-
poral differences in GABAergic neuron activity. We have
shown that GABAergic sIPSC frequencies recorded in lam-
ina II neurons have a big variation, and GABAeric sIPSC
frequency and tonic current size are correlated. It is very
likely that neurons with higher GABAergic sIPSC fre-
quency have higher concentrations of ambient GABA
around them due to more frequent spillover of GABA
from inhibitory synapses. Therefore, these neurons have
larger-sized tonic inhibitory currents mediated by extra-
synpatic GABAA receptors. This is consistent with previous


QPC QTC
Figure 4
Charge transfers mediated by phasic inhibitory cur-
rents and by tonic inhibitory currents. A). Diagram illus-
trates the measurement of phasic inhibitory current charge
transfer (QPC) and tonic inhibitory current charge transfer
(QTc). B). Bar Graph shows the comparison between QPc
and QTC (n = 32). Tonic currents were revealed by the appli-
cation of 20 pM bucuculline. Strychnine was not included in
bath solution.



studies in cerebellar granule cells, which shows that ambi-
ent GABA concentration is maintained by action poten-
tial-dependent vesicular release and is responsible for
tonic GABAA receptor activation [1,7,20-23].

Although phasic inhibition is mediated by both GABAA
and glycine receptors in spinal cord lamina II of adult
mice, we did not observe any contribution of glycine
receptors to tonic inhibitory currents. The lack of glycine
receptor-mediated tonic inhibitory currents could be
mainly due to the lack of high affinity glycine receptor iso-
forms. Of different glycine receptor isoforms (alp, a23,
a33) identified in the CNS, their EC50 values for glycine
were normally above 50 jiM [24]. In contrast, extrasynap-
tic GABA receptors that contribute to tonic currents were
found to be high affinity isoforms (e.g. aoP6, a,4x8 and
U5 xY2) with EC50 in nanomolar range [6].

The large charge transfer carried by GABAergic tonic
inhibitory currents shown in this study indicates a persist-
ent increase in the input conductance of lamina II dorsal
horn neurons. The increase of input conductance in neu-
rons can decrease the size and duration of the excitatory
postsynaptic potentials (EPSPs), and make neurons less
likely to generate action potentials. Indeed, tonic currents
have been shown to be a critical determinant that controls
neuron excitability in cerebellar granule cells [7-9]. In spi-
nal cord lamina II, decreases of neuron excitability by
GABAergic tonic inhibitory current may be an important



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Bicuculline
Strychnine
S 50p)
..............1..... 0 s


*20.........PA
200 ms
...................... ..r ^ W^ WfS .^r


Molecular Pain 2006, 2:36








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mechanism to control nociceptive inputs and to prevent
central hyper-sensitization.


Competing interests
The authors) declare that they have no competing inter-
ests.


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