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Volume 16, Number 20,
Issue of October 15, 1996
pp. 6414-6423
Copyright ©1996 Society for Neuroscience
Excitatory GABA Responses in Embryonic and Neonatal Cortical
Slices Demonstrated by Gramicidin Perforated-Patch Recordings and
Calcium Imaging
David F. Owens,
Leslie H. Boyce,
Marion B. E. Davis, and
Arnold R. Kriegstein
Department of Neurology and The Center for Neurobiology and
Behavior, College of Physicians and Surgeons of Columbia University,
New York, New York 10025
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Gramicidin perforated-patch-clamp recordings in brain slices
were used to obtain an accurate assessment of the developmental change
in the GABAA receptor reversal potential
(EGABAA) in embryonic and early
postnatal rat neocortical cells including neuroepithelial precursor
cells, cortical plate neurons, and postnatal neocortical neurons. Our
results demonstrate that there is a progressive negative shift in
EGABAA, with the most positive
values found in the youngest cortical precursor cells. At the early
stages of neocortical development,
EGABAA is determined by the chloride
(Cl ) gradient, and the internal chloride concentration
([Cl]i) decreases with development.
EGABAA is positive to the resting
potential, indicating that GABA serves to depolarize developing
neocortical cells. Consistent with this conclusion, GABAA
receptor activation with muscimol was found to increase the internal
calcium concentration ([Ca2+]i) in both
embryonic and early postnatal neocortical cells through the activation
of voltage-gated calcium channels (VGCCs). Postnatal cells exhibit
spontaneous postsynaptic synaptic currents, which are eliminated by
bicuculline methiodide (BMI) but not glutamate receptor antagonists and
reverse at the Cl equilibrium potential. Likewise, brief
spontaneous increases in [Ca2+]i, sensitive
to BMI and TTX, are observed at the same ages, suggesting that
endogenous synaptic GABAA receptor activation can
depolarize cells and activate VGCCs. These results suggest that
GABAA receptor-mediated depolarization may influence early
neocortical developmental events, including neurogenesis and
synaptogenesis, through the activation of Ca2+-dependent
signal transduction pathways.
Key words:
cortical development;
GABA;
intracellular calcium;
perforated-patch recording;
neocortex;
synaptogenesis
INTRODUCTION
GABA is the principal inhibitory neurotransmitter
in the adult neocortex. It has been shown recently that
GABAA receptors are expressed early in cortical development
on proliferating neuroepithelial cells in the embryonic ventricular
zone (VZ) (LoTurco and Kriegstein, 1991 ; LoTurco et al., 1995) as well
as on immature neurons in the cortical plate (CP) (LoTurco and
Kriegstein, 1991; Araki et al., 1992; Laurie et al., 1992; Poulter et
al., 1992). Several studies have reported that GABAA
receptor activation depolarizes embryonic neuroblasts and neonatal
cortical neurons (Luhmann and Prince, 1991; LoTurco et al., 1995).
Likewise, GABA application has been shown to increase
[Ca2+]i in developing neocortical cells by
activation of voltage-gated Ca2+ channels (Yuste and Katz,
1991; Lin et al., 1994; LoTurco et al., 1995). GABA also can depolarize
adult neocortical neurons when applied to distal dendrites (Connors et
al., 1988; Staley et al., 1995). However, the mechanism underlying
depolarization may be different in immature and adult cortical neurons.
GABAA-mediated depolarization in immature neurons is
thought to be attributable to a high [Cl]i,
possibly maintained by unopposed inward Cl transport
(Luhmann and Prince, 1991; LoTurco et al., 1995). In more mature
neurons, GABA depolarization might be attributable to a high
[Cl]i in dendritic compartments (Deisz and
Luhmann, 1995) or could result from conductance of another anion
through the GABAA channel such as bicarbonate (Staley et
al., 1995). Because the role of GABA during early stages of
corticogenesis is likely to depend on its effect on membrane potential,
it is important to clarify the mechanism of GABA depolarization in
embryonic and neonatal cortical neurons. To study cellular chloride ion
gradients in situ, we used a perforated-patch-recording
method applied to slices and explants of embryonic and neonatal rat
cortex.
The GABAA receptor is primarily a chloride
(Cl) ionophore (Bormann et al., 1987); therefore, an
accurate characterization of the GABAA-mediated
depolarization in developing neocortical cells requires an intact
[Cl]i. Sharp electrode recording, which may
not significantly alter the intracellular ionic composition, cannot be
applied to very small, fragile cells. Whole-cell patch-clamp recording
is well-suited to recording from small cells but perturbs intracellular
ionic concentrations by dialyzing cytoplasmic contents. The method of
perforated-patch recording can circumvent these limitations. The most
commonly used ionophores (i.e., amphotericin B and nystatin), however,
create pores that are permeable to Cl (Marty and
Finkelstein, 1975; Horn and Marty, 1988). In contrast, gramicidin has
been shown to form membrane pores that are exclusively permeable to
monovalent cations and small, uncharged molecules (Hladky and Haydon,
1972; Myers and Haydon, 1972), thus allowing for patch-clamp recordings
that leave the [Cl]i undisturbed (Abe et
al., 1994; Ebihara et al., 1995; Kyrozis and Reichling, 1995). To
better understand the role of GABA during cortical development, we used
the gramicidin perforated-patch technique to study the membrane effects
of GABAA receptor activation in populations of embryonic
and neonatal cortical cells.
MATERIALS AND METHODS
Tissue preparation. Gravid rats (Sprague Dawley) were
anesthetized with an intraperitoneal injection of ketamine (50 mg/kg),
and embryos were exposed by cesarean section. Animals were decapitated,
and heads were placed immediately in iced artificial CSF (ACSF)
containing (in mM): 124 NaCl, 5 KCl, 1.25 NaH2PO4, 2 MgSO4, 2 CaCl2, 26 NaHCO3, and 10 glucose, oxygenated
with 95% O2/5% CO2, pH 7.4. Cerebral
hemispheres or whole brains were removed, and for experiments requiring
brain slices, tissue was embedded in warm (28-30°C) 1% low-melting
agarose (Fisher Scientific, Fair Lawn, NJ) in ACSF, hardened on ice,
and sliced into coronal sections with a vibratome (300-400 µm). For
some experiments, telencephalic hemispheres were not sliced but
prepared as slabs of neocortex by trimming off the hippocampus and
striatal anlage. Postnatal rat pups [postnatal age 0 (P0) to P2] were
anesthetized by hypothermia or intraperitoneal injection of ketamine
(50 mg/kg) and rapidly decapitated. Brains were removed and placed in
ice-cold ACSF oxygenated with 95% O2/5% CO2
and sliced coronally with a vibratome (300-400 µm). Slices were
confined to the sensorimotor regions of the cortex. Tissue was kept in
oxygenated ACSF at room temperature (RT) (21-23°C) for at least 1 hr
before recording.
Electrophysiological recordings. Patch-clamp recordings were
obtained at RT from cells in both slices and slabs of neocortex
continuously superfused with 95% O2/5% CO2
oxygenated ACSF. Methods for in situ patch-clamp recording
have been described previously (Blanton et al., 1989). Briefly,
electrodes (8-12 M ) were lowered onto the surface of a cortical
slice or explant and slowly advanced until a resistance increase was
detected (10-50 M), after which a suction pulse was applied
immediately to form a tight seal (2-40 G). To establish whole-cell
recording, additional suction was applied to rupture the underlying
plasma membrane. Perforated-patch recordings (Abe et al., 1994; Ebihara
et al., 1995; Kyrozis and Reichling, 1995) were obtained using
identical methods, except mechanical rupture of the plasma membrane was
omitted. The progress of perforation was evaluated by monitoring the
decrease in the membrane resistance. Drugs were applied after the
membrane resistance had stabilized; this usually took from 1 to 10 min.
Gramicidin (Sigma, St. Louis, MO) was dissolved in dimethylsulfoxide
(DMSO) (Sigma) (1-2 mg/ml) then diluted in the pipette filling
solution to a final concentration of 0.2-5 µg/ml. In some
experiments, perforated-patch recordings were converted to whole-cell
recordings by applying suction to rupture the underlying plasma
membrane. For the majority of recordings, patch electrodes were filled
with a solution containing (in mM): 100 CsCl, 30 Cs
gluconate, 10 HEPES, pH 7.3, 2 CaCl2, and 11 EGTA. To test
different concentrations of Cl in the pipette solution
([Cl]p), whole-cell recordings were made
with gluconate substituted for Cl in the filling
solution. In some whole-cell recordings, a KCl filling solution was
used containing (in mM): 130 KCl, 5 NaCl, 0.4 CaCl2, 1 MgCl2, 10 HEPES, pH 7.3, and 1.1 EGTA.
Liquid junction potentials for the CsCl and KCl filling solutions
(Neher, 1992) were  4.7 and 3.4 mV, respectively. In CsCl filling
solutions in which gluconate substituted for Cl, liquid
junction potentials were 6.8 and 9.1 mV for a 54 mM
Cl solution and a 20 mM Cl
solution, respectively. Data from experiments that tested different
concentrations of [Cl]p were corrected for
liquid junction potentials (see Fig. 4C). When using voltage
ramps, recordings were digitized and analyzed with pClamp software
(Axon Instruments, Foster City, CA). The voltage-ramp protocol
consisted of stepping the cell from a holding potential of 60 to +20
or +40 mV for 80 msec, then changing the voltage to 100 mV at a rate
of 150 mV/sec. I-V curves were plotted after
subtracting the control response obtained in ACSF from the response
obtained during agonist application. In these experiments, the
GABAA reversal potential was defined as the
x-intercept value of the muscimol-induced current. GABA (30 µM) was applied with the membrane held at a series of
potentials. Peak current responses for each voltage were plotted, and
the data were fit using CA-Cricket Graph III software (Computer
Associates). The GABA-mediated reversal potential was defined as the
x-intercept value of the fit. Unless noted, the bath ACSF in
experiments using ramp voltage clamp contained La3+ (30 µM) to block voltage-gated calcium channels (VGCCs)
(Reichling and MacDermott, 1991). In all experiments, TTX (2 µM) was added if voltage-activated Na+
currents were detected, and potassium (K+) conductances
were blocked by cesium (Cs+) (130 mM) in the
pipette filling solution. In some experiments, recordings were
performed in a bicarbonate-free, HEPES-buffered saline solution
containing (in mM): 124 NaCl, 5 KCl, 1.25 NaH2PO4, 26 HEPES, 2 MgSO4, 2 CaCl2, and 10 glucose, pH 7.4, bubbled with 100%
O2. For all experiments, average values are expressed as
mean ± SEM.
Fig. 4.
Cl gradient contributes
significantly to EGABAA.
A, Wholecell recording with different
[Cl]p (104 mM,
n = 3; 52 mM, n = 4; 20 mM, n = 3) yielded reversal
potentials comparable to those predicted by the Nernst equation
(dashed line). Recordings were from P4 neocortical
neurons; no La3+ was present in these experiments. These
data were corrected for liquid junction potentials that were determined
experimentally for each solution. B, Absence of a
developmental shift in EGABAA using
whole-cell recordings ([Cl]p = 104 mM). EGABAA measured in
E16 CP cells (3.9 ± 1.3 mV, n = 5) and P4 neocortical cells (6.4 ± 1.0 mV,
n = 3) had values close to that predicted by the
Nernst equation (6.2 mV) (open square).
C, Furosemide (2 mM) application produced a
negative shift (8.1 ± 0.9 mV, n = 3) in
EGABAA determined with
perforated-patch recordings from E16 CP cells.
EGABAAfor each cell was determined
both before and after furosemide application, with the average values
being 42.4 ± 1.8 and 50.4 ± 1.1 mV, respectively.
[View Larger Version of this Image (9K GIF file)]
Calcium imaging in brain slices using fluo-3. Coronal slices
were prepared as described above. Cells were loaded in the dark with
the Ca2+ indicator dye fluo-3 by immersion for 60 min in
ACSF containing the acetomethylester form of fluo-3 (fluo-3AM) (10 µM) followed by ACSF wash. Slices were placed in a
perfusion chamber on the stage of a Zeiss Axiovert microscope (40×,
numerical aperture 0.75 objective) with a Bio-Rad (Hercules, CA)
MRC-600 argon laser scanning confocal attachment. Excitation was at 488 nm, and emissions were collected using a 515 nm long-pass emission
filter. Neutral density filters were used to filter the argon laser
light to 1% to minimize photobleaching. Images were acquired at 1.0 sec/frame, and two frames were averaged for each image. Considering the
2 sec download time, images were acquired at either 4.0 sec/image or
5.0 sec/image. Images were acquired on an IBM compatible computer
running Comos acquisition software (Bio-Rad). Fluorescence micrographs
were digitized, and relative changes in
[Ca2+]i from randomly selected cells were
measured using the public domain National Institutes of Health (NIH)
Image program (written by Wayne Rasband at NIH) on a Macintosh 7200 computer. Data are expressed as a change in fluorescence over baseline
fluorescence ( F/F). A microscopic field
was visualized and perfused with drug-free medium while three images
were obtained and averaged to obtain the baseline value F.
Each subsequent image during drug application and washout was processed
and expressed as a change in fluorescence over baseline fluorescence by
F/F. For experiments measuring spontaneous
[Ca2+]i fluctuation, F was defined
as the frame with the minimum level of fluorescence. In solutions that
used Cd2+, 2 mM HEPES replaced
NaH2PO4 in the ACSF. Average values are
expressed as mean ± SEM.
Pharmacological agents. Muscimol, furosemide, bicuculline
methiodide (BMI), lanthanum (La3+), cadmium
(Cd2+), and TTX were obtained from Sigma; GABA,
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and
2-amino-5-phosphonopentanoic acid (AP-5) were obtained from RBI
(Natick, MA). In electrophysiological experiments, GABA, muscimol, BMI,
and AP-5 were applied by focal puffer application (DAD-12 Superfusion
System, ALA Scientific Instruments, Westbury, NY). Furosemide,
La3+, CNQX, and TTX were bath-applied. In Ca2+
imaging studies, all drugs were bath-applied. Drugs were kept as
concentrated stock solutions at 20°C (muscimol, BMI, CNQX, AP-5,
Cd2+, and GABA) or 4°C (La3+ and TTX) and
diluted to the desired concentration on the day of the experiment.
Furosemide was dissolved directly in ACSF. Fluo-3AM was obtained from
Molecular Probes (Eugene, OR).
RESULTS
Gramicidin perforated-patch recording in brain slices
Comparing perforated-patch with whole-cell recording in the same
cell confirmed the importance of [Cl]i in
determining GABA-mediated responses. An example is shown in Figure
1. A gramicidin perforated-patch recording from an
embryonic day 19 (E19) CP neuron was obtained, and GABA (30 µM) was applied focally with the membrane potential held
at 60 mV and again at 30 mV (Fig.
1A,B, left traces). The
perforated patch was converted into a whole-cell recording by applying
suction, and GABA was reapplied (Fig.
1A,B, right traces). As
shown in Figure 1C, the reversal potential for the
perforated-patch recording was approximately 40 mV. In the whole-cell
configuration, the reversal potential was ~0 mV, close to the
potential predicted by the Nernst equation (i.e., 6.2 mV), given the
[Cl]p and assuming complete exchange with
the cell cytoplasm. These data confirm that the gramicidin
perforated-patch method does not allow Cl to cross the
patch membrane.
Fig. 1.
Comparison of gramicidin perforated-patch and
whole-cell recordings in the same cell. A,
B, The GABA (30 µM)-induced current was
measured in an E19 CP cell at holding potentials
(Vh) of 60 and 30 mV with a gramicidin
perforated patch (traces at left). The recording was
subsequently converted to a whole-cell recording, and GABA application
was repeated (traces at right). C, The
I-V relationship of GABA-induced
currents is illustrated for both methods of recording. With the
perforated patch, the GABA reversal potential was approximately 40 mV
(circles), whereas in whole-cell mode, the reversal
potential shifted to ~0 mV (squares), close to the
value predicted by the Nernst equation.
[View Larger Version of this Image (10K GIF file)]
EGABAA shifts to more negative
potentials during development
Gramicidin perforated patches and muscimol (30 µM)
application were used to determine the GABAA reversal
potential in embryonic CP cells and early postnatal neocortical
neurons. When cortical neurons undergo their final mitosis and migrate
out of the VZ, they are small, electrically compact, have small
processes, and are no longer coupled to VZ cells; these features
provide favorable conditions for voltage-clamp studies. Figure
2A is an example of the voltage-ramp
protocol applied to measure the GABAA reversal potential of
an E19 CP cell, with the resulting current-voltage
(I-V) curve shown in Figure
2B. For comparison, Figure 2B also
shows the GABAA I-V curve derived
from an E16 CP cell in whole-cell mode. Similar results were found in a
second series of experiments that used the natural ligand GABA as
agonist. GABA (30 µM) was applied focally to cells held
at a series of membrane potentials, and I-V
curves were constructed. Figure 2C shows an example of the
I-V relationship of the GABA-induced response
for a P2 neocortical neuron. The reversal potential is approximately
52 mV. In contrast, more mature neurons had more negative reversal
potentials, as shown in Figure 2D for a P16 neuron
with a GABA reversal potential of approximately 66 mV. GABA
applications at P16 could produce complicated responses consisting of
two or more phases (Fig. 2D, inset),
presumably attributable to the maturation of the GABAB
receptor subtype (Luhmann and Prince, 1991). When multiple components
were present, the shortest latency peak current was the value used in
the GABA I-V curve.
Fig. 2.
EGABAA was
determined either by muscimol (30 µM) application and
voltage ramps or by GABA (30 µM) application with the
membrane held at a series of potentials. A, Voltage-ramp
protocol applied to an E19 CP cell. B, The resulting
I-V curve obtained from the recording in
A after control-ramp subtraction.
EGABAA is approximately 40 mV. For
comparison, an I-V curve obtained from
an E16 CP cell in whole-cell mode is shown. C,
I-V relationship for a P2 neocortical
neuron with a reversal potential of approximately 52 mV. The
inset shows the GABA-induced current at two membrane
potentials. Note the monophasic response at both holding potentials.
D, I-V relationship for a
P16 neocortical neuron with a reversal potential of approximately 66
mV. The inset shows the GABA-induced current at two
membrane potentials. Note the greater complexity of the response at the
60 mV holding potential.
[View Larger Version of this Image (21K GIF file)]
The earliest cells in the neocortex to express functional
GABAA receptors are the proliferating neuroepithelial cells
in the embryonic VZ (LoTurco et al., 1995). Because the proliferating
VZ cells are electrically coupled to each other through gap junction
channels (LoTurco and Kriegstein, 1991), the ability to voltage-clamp
the membrane of a single cell and to measure
EGABAAis limited by the large area
of membrane composing a coupled cell cluster. There is evidence that at
least some neonatal cortical neurons also are electrically coupled by
dendrodendritic contacts to other cortical neurons in the first
postnatal week (Connors et al., 1983; Peinado et al., 1993);
nonetheless, voltage control over the soma and proximal dendritic
membrane is much better in neonatal cortical neurons, where it is
possible to obtain accurate reversal potentials for GABAA
responses, than in VZ cells, where GABAA reversal
potentials cannot be measured because of poor voltage control.
Therefore, we used an indirect approach to estimate a lower limit value
for the GABAA reversal potential in VZ cells. This
consisted of measuring the peak depolarization produced by a saturating
dose of muscimol using perforated-patch recordings. TTX (2 µM) and La3+ (30 µM) were added
to the bathing solution to block voltage-gated Na+ and
Ca2+ currents, respectively, and Cs+ (130 mM) was present in the electrode filling solution to block
K+ currents. The maximum depolarization, assuming blockage
of voltage-dependent conductances, represents an indirect measurement
of EGABAA. To determine the
saturating concentration of muscimol, recordings were obtained from E16
VZ cells in current-clamp mode. In these cells, 50 µM and
100 µM muscimol produced nearly identical levels of
depolarization (26.1 ± 3.6 mV for 50 µM muscimol
and 26.5 ± 4.2 mV for 100 µM muscimol,
n = 6), strongly suggesting that saturating responses
could be obtained with 100 µM muscimol. Muscimol (100 µM) depolarized VZ cells to an average membrane potential
of 32.2 ± 1.2 mV (n = 6). If intracellular
Cs+ was not able to reach all the cells in a coupled
cluster, activation of voltage-activated K+ currents in
cells coupled to the recorded cell would lead to an underestimate of
the true level of depolarization. This methodology, therefore, gives an
estimate of the lower limit value for the GABAA reversal
potential.
Considering the close agreement between the reversal potentials
obtained with either GABA or muscimol as an agonist, these data were
combined to provide a developmental time course for the changes in the
reversal potential for the GABAA receptor-mediated current
(Fig. 3A). Measurements made over a 3 week
developmental period demonstrate that at embryonic stages, the average
GABAA reversal potential was considerably less negative
(32.2 ± 1.2 mV for VZ cells at E16 and 38.2 ± 2.0 mV
for CP cells at E16) than at later developmental periods (61.3 ± 3.7 mV at P16). Because GABAB receptor-mediated
responses are not readily detected until the second postnatal week
(Luhmann and Prince, 1991), activation of both GABAA and
GABAB receptors by GABA application probably would occur
only for recordings performed at P16. However, when multiphasic GABA
responses were observed at P16, measurements were taken from the peak
of the initial phase of the response, which is mediated by
GABAA receptors (Connors et al., 1988).
Fig. 3.
There is a progressive negative shift in
EGABAA over development.
A, Pooled reversal potentials derived from experiments
using either GABA or muscimol as agonist. Also plotted are the resting
membrane potentials (ERest) (see Results).
Because resting potential measurements for VZ and CP cells were made on
E15-E17 and E18-E19, respectively, their placement on the graph
is approximate. For EGABAA,
n = 6 for E16 VZ; n = 14 for
E16 CP; n = 22 for E19 CP; n = 3 for P0; n = 5 for P1; n = 3 for P2; n = 7 for P4; n = 5 for
P16. B, [Cl]i calculated
from combined data in A using the Nernst equation.
Values are as follows, E16 VZ, 37.0 mM; E16 CP, 29.2 mM; E19 CP, 23.8 mM; P0, 19.4 mM;
P1, 18.8 mM; P2, 20.0 mM; P4, 18.8 mM; P16, 11.7 mM.
[View Larger Version of this Image (15K GIF file)]
GABA responses are depolarizing because of high
[Cl]i
The effect of GABA or muscimol on the membrane potential of an
individual neuron at a given age will depend both on the reversal
potential for the agonist-induced current and on the resting membrane
potential of the cell. To accurately measure
EGABAA, our perforated-patch
electrode solution contained Cs+ to block voltage-dependent
K+ currents, but this also may bias the resting potential
to more positive values. Therefore, resting potential measurements with
a Cs+-based pipette solution are difficult to interpret. To
circumvent this problem, whole-cell recordings with KCl-filled
electrodes were used to measure the resting membrane potential in the
same cell populations in which
EGABAA was determined. The average
resting potential was 55.3 ± 1.2 mV in embryonic VZ cells (E15
and E17, n = 10), 65.0 ± 1.7 mV in embryonic CP
cells (E18 and E19, n = 15), and 64.0 ± 4.3 mV
in P3 cortical neurons (n = 6), as shown in Figure
3A. Given that these resting membrane potentials are more
negative than EGABAA at the
corresponding ages, GABAA receptor activation would produce
membrane depolarization in these populations of embryonic and neonatal
cortical cells.
Depolarizing GABA responses have been attributed to a number of
different mechanisms including high [Cl]i
(Luhmann and Prince, 1991), an increase in conductance to another anion
such as bicarbonate (Kaila and Voipio, 1987; Kaila et al., 1989; Staley
et al., 1995), or, possibly, a cation conductance (Andersen et al.,
1980). Recent evidence in immature neurons has suggested that the
Cl gradient may be the dominant contributor to
GABAA-induced depolarization (Reichling et al., 1994; Wang
et al., 1994; Rohrbough and Spitzer, 1996). The contribution of the
[Cl]i to
EGABAA- and
GABAA-mediated depolarization in immature cortical neurons
was investigated in several ways. First, whole-cell recordings were
used to bias the [Cl]i to that of the
pipette for three different [Cl]p values,
and the muscimol-induced reversal potentials were measured. These
values were compared with the reversal potential for Cl
predicted by the Nernst equation. As shown in Figure
4A, the experimental data fit the
predicted values for the Cl gradient across the membrane,
supporting the hypothesis that Cl is the principle ion
mediating the GABAA receptor effect. Furthermore, despite
the developmental shift in the GABAA reversal potential
determined with perforated-patch recordings (see Fig. 3A),
the GABAA reversal potential measured by whole-cell
recording remained close to that predicted by the Nernst equation (Fig.
4B), confirming that
[Cl]i is chiefly responsible for setting
the GABAA reversal potential during this developmental
period. To test whether bicarbonate ions are responsible for
muscimol-induced inward current, perforated-patch recordings were
obtained from E19 CP cells in bicarbonate-free, HEPES-buffered saline.
Muscimol application still produced an inward current at a holding
potential of 60 mV, a potential close to the average resting
potential determined with KCl-filled electrodes. The average
EGABAA measured under these
conditions was 41.0 ± 5.1 mV (n = 4) (data not
shown). This suggests that bicarbonate ions are not necessary for
GABAA-mediated inward currents at this age. Lastly, the
GABAA reversal potential was determined using
perforated-patch recordings, and then furosemide (2 mM), a
Cl transport blocker, was applied to perturb the
[Cl]i. The muscimol-induced reversal
potential in E16 CP cells shifted an average of 8.1 ± 0.9 mV more
negative in the presence of furosemide, consistent with a dependence of
the muscimol response on a high [Cl]i
maintained by a Cl transport process (Fig.
4C). Taken together, these data indicate that the
GABAA reversal potential is mediated predominantly by
Cl flux in embryonic and neonatal cortical neurons. These
findings allow use of the Nernst equation to estimate
[Cl]i in embryonic and neonatal cells based
on the GABA and muscimol-reversal potential data (Fig. 3B).
GABAA receptor activation increases
[Ca2+]i by activating VGCCs
One possible consequence of membrane depolarization could be an
increase in [Ca2+]i mediated by the
activation of VGCCs. Previous results from our laboratory have
demonstrated that GABA application produces increases in
[Ca2+]i in embryonic VZ cells (LoTurco et
al., 1995). In light of the present analysis of the GABAA
reversal potential, we extended our Ca2+ imaging studies to
embryonic CP and early postnatal neocortical cells. Figure
5A1-A3 shows that muscimol (30 µM) application produced a reversible increase in
[Ca2+]i in CP cells at E17. Eight cells were
randomly chosen from the microscopic field, and the increases in
[Ca2+]i were calculated and expressed as
F/F (see Materials and Methods); these results
are shown in Figure 5B. Similarly, increases in
[Ca2+]i were found in early postnatal
neocortical cells. Figure 5C shows the mean change in
[Ca2+]i for eight cells from a P2 neocortical
slice after application of 30 µM muscimol. After a 30 min
recovery period, a second muscimol application, in the presence of 500 µM Cd2+, failed to elicit
[Ca2+]i increases in the same cells,
suggesting that the GABAA receptor-mediated increase in
[Ca2+]i results from the activation of VGCCs.
A similar level of blockade was found when using 30 µM
La3+ (data not shown). These results are consistent with
GABAA-mediated increases in
[Ca2+]i reported in similar studies carried
out in developing rat visual cortex (Yuste and Katz, 1991; Lin et al.,
1994).
Fig. 5.
Muscimol (30 µM) produces increases
in [Ca2+]i in developing cortical cells.
A, Confocal image of E17 CP cells loaded with the
Ca2+ indicator fluo-3AM before (1), during
(2), and after (3) application of
muscimol (30 µM). Pial surface is to the
top of the image. B, Eight cells were
randomly chosen from the microscopic field in A, and the
increases in [Ca2+]i were calculated,
averaged, and expressed as mean F/F
(see Materials and Methods). C, Mean change in
[Ca2+]i for eight randomly selected cells
from a P2 neocortical slice after application of 30 µM
muscimol (squares). After a 30 min recovery period, a
second muscimol application, in the presence of 500 µM
Cd2+, failed to elicit [Ca2+]i
increases in the same cells (circles).
[View Larger Version of this Image (46K GIF file)]
sPSCs and [Ca2+]i increases are
GABAA-mediated
Under conditions of whole-cell recording, spontaneous synaptic
activity was observed in neocortical neurons. In 25 recordings from
P1-P4 slices, 72.0% of the cells had resolvable sPSCs. The sPSCs were
not blocked when the non-NMDA receptor antagonist CNQX (10 µM) was present in the bath solution (n = 12). However, in the continued presence of CNQX, the sPSCs were
abolished when BMI (10 µM) was applied focally
(n = 9) (Fig. 6A) but
not when the NMDA receptor antagonist AP-5 (100 µM) was
applied (n = 7). This suggests that the majority of the
early postnatal sPSCs are mediated by activation of GABAA
receptors. TTX (2 µM) also could eliminate the sPSCs,
indicating that they are action potential-dependent (n = 3). We compared the reversal potential of the muscimol-induced
current with the reversal potential of the GABAA-mediated
sPSC in three cells. An example from a P4 neocortical neuron is shown
in Figure 6. sPSCs were collected at each of five membrane potentials
ranging from 80 mV to 40 mV. Fifteen to 30 sPSCs at each membrane
potential were averaged, and the peak current was plotted. The
approximate reversal potential for the averaged sPSCs was 4.1 mV
(Fig. 6B), whereas
EGABAA was found to be 5.4 mV
(Fig. 6C). Both of these values are close to that predicted
by the Nernst equation for the experimentally established
Cl gradient (i.e., 6.2 mV). This demonstrates that the
reversal potential for an endogenously active
GABAA-mediated synaptic current is nearly identical to the
reversal potential for the exogenously applied GABAA
agonist muscimol.
Fig. 6.
Activation of GABAA receptors by both
endogenously released GABA and exogenously applied muscimol (30 µM) yields similar reversal potentials. A,
Examples of sPSCs recorded in control conditions
(Control), during 10 µM BMI
application (BMI), and after BMI was washed out
(Wash). Application of AP-5 (100 µM) did
not abolish the sPSCs (data not shown). All recordings are in the
presence of 10 µM CNQX in the bath solution.
Vh = 60 mV. B,
I-V curve derived from averaged sPSCs at
five membrane potentials with an approximate reversal potential of
4.1 mV. Inset shows averaged sPSCs at two membrane
potentials. C, The muscimol induced
I-V curve for the same cell as show in
B, with an EGABAA of
5.4 mV.
[View Larger Version of this Image (20K GIF file)]
Given the GABAA reversal potentials determined above
with perforated patches, spontaneous GABAA-mediated
synaptic potentials could depolarize neonatal neurons sufficiently to
activate VGCC and increase [Ca2+]i. To test
this idea directly, slices of early postnatal neocortex were imaged
using confocal laser microscopy. Figure 7A
shows the Ca2+ transients in a P1 neocortical cell. When
BMI (30 µM) was washed into the recording chamber, the
spontaneous events were reversibly blocked. Furthermore, TTX (2 µM) also could block the spontaneous increases in
[Ca2+]i, consistent with our physiological
findings that TTX can eliminate the BMI-sensitive sPSCs. Finally,
muscimol (30 µM) application produced an increase in the
[Ca2+]i in the same cell, indicating the
presence of GABAA receptors on this cell and confirming
their ability to produce [Ca2+]i increases.
Similar data were obtained for neocortical cells at P3 (Fig.
7B). At P3, we found that BMI blocked the spontaneous
[Ca2+]i increases in 77.8%
(n = 18) of the cells, and in 100% of these cells,
muscimol application produced increases in
[Ca2+]i. These results, in combination with
the GABAA reversal potentials determined with perforated
patches, suggest that in the early postnatal neocortex, spontaneous
GABAA-mediated depolarizing potentials produce
[Ca2+]i increases, presumably by the
activation of VGCCs.
Fig. 7.
Spontaneous increases in
[Ca2+]i in postnatal neocortical cells are
mediated by GABAA receptor activation. A,
Spontaneous Ca2+ transients in a P1 neocortical cell
(1) were reversibly blocked by BMI (30 µM)
(2, 3). TTX (2 µM) also
could eliminate the spontaneous increases in
[Ca2+]i (4). 2
Shows activity during wash in of bicuculline (indicated by the
dashed line), whereas 4 shows activity 3 min after wash in of TTX. The muscimol (30 µM)-mediated
increase in [Ca2+]i (5)
suggests the presence of GABAA receptors on this cell.
Breaks in the x-axis represent ~1, 10, 10, and 3 min,
respectively. B, Combined data from four P3 neocortical
cells. Each cell had at least one spontaneous increase in
[Ca2+]i during two control recording periods
(1, 2). In the presence of BMI, no
additional spontaneous increases in [Ca2+]i
were observed (3). BMI application began ~1 min before
data acquisition. As in A, muscimol (30 µM) application also produced
[Ca2+]i increases (4). Breaks
in the x-axis represent ~1, 1, and 8 min,
respectively.
[View Larger Version of this Image (21K GIF file)]
DISCUSSION
Depolarizing effects of GABA have been reported in immature
cells from a number of brain regions including the neocortex (Luhmann
and Prince, 1991), hippocampus (Ben-Ari et al., 1989; Cherubini et al.,
1990), spinal cord (Wu et al., 1992; Reichling et al., 1994; Wang et
al., 1994; Rohrbough and Spitzer, 1996), cerebellum (Connor et al.,
1987), olfactory bulb (Serafini et al., 1995), and retina (Yamashita
and Fukuda, 1993). In cortical neurons, most of these studies have been
performed using sharp intracellular electrodes, but these methods
cannot be applied to very immature neurons without causing significant
injury. Furthermore, one cannot assume that the intracellular ionic
composition is completely intact with sharp electrode recording.
Whole-cell voltage-clamp techniques are well-suited to recording from
small, fragile cells, but because cell contents exchange with the
electrode solution under whole-cell conditions, ion gradients across
the cell membrane are severely biased toward the pipette solution. The
use of perforated-patch recordings with an anion-impermeant ionophore
(Abe et al., 1994; Ebihara et al., 1995; Kyrozis and Reichling, 1995)
overcomes these limitations and allows accurate measurements of
EGABAA in small, immature cells. We
have applied this technique to examine developmental changes in
EGABAA in neocortical cells in
situ. The results show that
EGABAA becomes more negative as
cells mature, with the most positive values observed in the youngest
cortical precursor cells. The measured resting potentials of these
immature cells verify that GABAA receptor activation would
function to depolarize neurons during early development, and the
depolarization appears to be determined largely by the Cl
gradient, with the highest [Cl]i found in
embryonic cortical precursor cells and the
[Cl]i gradually decreasing as neurons
mature.
The mechanism of GABA depolarization may differ between immature
and adult cortical neurons
The depolarization mediated by GABA in developing cortical cells
contrasts, in some regards, with the GABA-mediated depolarization
found, under certain conditions, in adult cortical neurons (Alger and
Nicoll, 1982; Connors et al., 1988; Janigro and Schwartzkroin, 1988;
Lambert et al., 1991; Grover et al., 1993; Staley et al., 1995). In
adult cells, GABAA receptor activation by either
high-frequency stimulation or exogenous application of large amounts of
GABA can produce a biphasic response of hyperpolarization followed by
depolarization (Connors et al., 1988; Grover et al., 1993; Staley et
al., 1995). In this case, a bicarbonate conductance appears to play a
significant role in the depolarizing phase of the response (Staley et
al., 1995); however, other mechanisms have been proposed (Deisz and
Luhmann, 1995). In the present study, responses to exogenously applied
GABA or muscimol were monophasic; even with prolonged agonist
application, we never saw multiphasic responses, except at the very
latest time point studied (i.e., P16). Furthermore, in bicarbonate-free
saline, we observed inward currents when muscimol was applied to E19 CP
cells voltage-clamped close to the resting membrane potential. This
contrasts with results found in adult neocortical (Staley et al., 1995)
and hippocampal (Grover et al., 1993) pyramidal neurons in which GABA
application to the distal dendrites did not produce inward current or
membrane depolarization when recording in bicarbonate-free saline.
These results lead us to believe that the GABAA-mediated
depolarization in adult and developing neocortical cells may be
mechanistically distinct and that the Cl gradient is
primarily responsible for GABA-mediated depolarization in developing
cells. This is consistent with other developmental studies in
immature spinal cord neurons in which GABAA-mediated
depolarization has been shown to be primarily attributable to the
Cl gradient (Reichling et al., 1994; Rohrbough and
Spitzer, 1996). Furthermore, evidence has suggested that immature
neocortical neurons have less efficient Cl transport in
the outward direction (Luhmann and Prince, 1991), which can account for
higher [Cl]i and more positive
GABAA reversal potentials. Likewise, measurements of the
[Cl]i in cultured hippocampal neurons have
demonstrated that more immature cells have higher somatic
[Cl]i (Hara et al., 1992).
GABA may influence cortical development through
Ca2+-dependent mechanisms
GABAA-mediated spontaneous synaptic potentials can
occur early in postnatal development in both the neocortex and
hippocampus (Luhmann and Prince, 1991; Hosokawa et al., 1994). In the
neocortex, BMI-sensitive spontaneous synaptic events can precede evoked
GABAergic synaptic potentials (Luhmann and Prince, 1991). Furthermore,
in immature hippocampal neurons in slices, BMI application has been
shown to induce small hyperpolarizations in membrane potential,
suggesting that tonic GABA release can influence the resting membrane
potential (Ben-Ari et al., 1989; Hosokawa et al., 1994). Likewise,
hippocampal neurons in cell culture have been shown to tonically
release GABA by an action potential-independent mechanism (Valeyev et
al., 1993). The early maturation of GABA release mechanisms as well as
the early development of spontaneous GABAA-mediated
synaptic events well before development of synaptic inhibition supports
the notion that GABA has a functional role in nervous system
development. GABA even may have an influence on the key processes of
proliferation, migration, and differentiation. Recently, GABA has been
shown to influence DNA synthesis in cortical precursor cells through
activation of GABAA receptors (LoTurco et al., 1995). In
addition, GABA has been shown to have a variety of effects on the
migratory behavior of young postmitotic neurons grown in tissue culture
(Behar et al., 1994, 1996). Also, GABA has been shown to induce
morphological changes (Barbin et al., 1993) and alter neurotrophic
factor expression (Berninger et al., 1995) in cultured hippocampal
neurons.
Many of the trophic actions of GABA in cortical cells may be mediated
by calcium-dependent mechanisms. In this study, as well as others
(Yuste and Katz, 1991; Lin et al., 1994; LoTurco et al., 1995),
exogenous GABA or muscimol application has been shown to increase
[Ca2+]i in immature neocortical cells through
the activation of VGCCs. We have demonstrated that BMI application can
reversibly block spontaneous increases in
[Ca2+]i in early postnatal neocortical
neurons, suggesting that spontaneous GABAA-mediated
synaptic potentials may depolarize cells sufficiently to activate
VGCCs. This is likely to be an age-related phenomenon, because synaptic
GABAA receptor activation has been shown to increase
[Ca2+]i in P2-P5 but not P12-P13
hippocampal neurons (Leinekugel et al., 1995). We have not
characterized the type(s) of VGCC expressed by immature cortical
neurons, but it has been suggested that low-threshold VGCCs are
responsible for GABA-induced [Ca2+]i
increases in these cells (Yuste and Katz, 1991). Calcium entry via
GABA-mediated VGCC activation has been shown to upregulate
brain-derived neurotrophic factor (BDNF) expression in immature
hippocampal neurons (Berninger et al., 1995). In cultured embryonic
cortical neurons, activation of VGCCs but not glutamate channels
increased neuronal survival, an effect that correlated with increased
BDNF expression (Ghosh et al., 1994). Finally, muscimol application has
been found to regulate the phenotype of immature hippocampal
interneurons, an effect that may be mediated through the regulation of
BDNF expression and release from target cells (Marty et al., 1996).
There is mounting evidence that GABA may act as a trophic factor in
early development by depolarizing cells, activating VGCCs, and, in
turn, regulating gene expression through the activation of
Ca2+-dependent second messenger pathways.
As shown in this study, GABA continues to have depolarizing effects at
early postnatal stages. The transient BMI-sensitive spontaneous
[Ca2+]i increases observed in neonatal
cortical slices reported here may represent the activity of
early-forming GABAergic synapses. The potential for early GABAergic
synapses to depolarize postsynaptic cells and activate Ca2+
entry raises the possibility that the establishment or strengthening of
inhibitory synapses may involve similar mechanisms to those involved in
the formation of activity-dependent excitatory contacts
(Constantine-Paton et al., 1990; Cline, 1991). Recent evidence in adult
hippocampus has suggested that GABAA receptor-mediated
depolarization is able to increase the conductance of the NMDA
receptor, possibly by relieving the Mg2+ block of the
channel (Staley et al., 1995). Furthermore, a novel form of
GABA-dependent long-lasting potentiation has been reported in the
hippocampus of genetically altered mice (Frey et al., 1996). Thus, it
appears that GABA may play a role in adult forms of synaptic plasticity
and also may regulate plastic events during development.
FOOTNOTES
Received May 17, 1996; revised July 18, 1996; accepted July 24, 1996.
This work was supported in part by Research Grant FY95-0879 from the
March of Dimes Birth Defects Foundation, National Institutes of Health
Grant NS 21223, and Neurological Sciences Academic Development Award
NS01698 to L.H.B. We thank Cristovao de Albuquerque, Amy MacDermott,
and Gareth Tibbs for helpful comments on this manuscript, and Alexander
Flint for helpful comments and assistance with computer graphics.
Correspondence should be addressed to Dr. Arnold R. Kriegstein,
Department of Neurology, College of Physicians and Surgeons of Columbia
University, 630 West 168th Street, P.O. Box 31, New York, NY
10032.
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Compound via MeSH
