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The Journal of Neuroscience, April 1, 1999, 19(7):2546-2555
Noninvasive Measurements of the Membrane Potential and GABAergic Action in Hippocampal Interneurons
Jos A. H. Verheugen, Desdemona Fricker, and Richard Miles Laboratoire de Neurobiologie Cellulaire et Moleculaire, Institut National de la Santé et de la Recherche Médicale U261, Institut Pasteur, 75724 Paris, France
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
Neurotransmitters affect the membrane potential (Vm) of target cells by modulating the activity of receptor-linked ion channels. The direction and amplitude of the resulting transmembrane current depend on the resting level of Vm and the gradient across the membrane of permeant ion species. Vm, in addition, governs the activation state of voltage-gated channels. Knowledge of the exact level of Vm is therefore crucial to evaluate the nature of the neurotransmitter effect. However, the traditional methods to measure Vm, with microelectrodes or the whole-cell current-clamp technique, have the drawback that the recording pipette is in contact with the cytoplasm, and dialysis with the pipette solution alters the ionic composition of the interior of the cell. Here we describe a novel technique to determine the Vm of an intact cell from the reversal potential of K+ currents through a cell-attached patch. Applying the method to interneurons in hippocampal brain slices yielded more negative values for Vm than subsequent whole-cell current-clamp measurements from the same cell, presumably reflecting the development of a Donnan potential between cytoplasm and pipette solution in the whole-cell mode. Cell-attached Vm measurements were used to study GABAergic actions in intact CA1 interneurons. In 1- to 3-week-old rats, bath-applied GABA inhibited these cells by stabilizing Vm at a level depending on contributions from both GABAA and GABAB components. In contrast, in 1- to 4-d-old animals, only GABAA receptors were activated resulting in a depolarizing GABA response.
Key words: hippocampus; interneuron; potassium channels; cell-attached patch-clamp; membrane potential; GABA
INTRODUCTION
GABA is the principal inhibitory neurotransmitter in the mammalian brain. Chloride-permeable channels, with a substantial permeability also for HCO3
(Bormann et al., 1987
), open when GABA binds to GABAA receptors (Ozawa and Yuzaki, 1984
These problems may be avoided using a noninvasive approach, based on the reversal potential of K+ currents through cell-attached patches, to measure Vm (Verheugen et al., 1995
Vh) equals Vm. Repetitive measurements of K(V) reversal in the cell-attached mode may then be used to follow fluctuations in Vm. Furthermore, changes in K(V) reversal during exposure to GABA and selective agonists of GABAA and GABAB receptors can provide estimates of respectively EGABA, EGABA-A, and EGABA-B, or at least (in the case other conductances still significantly contribute in setting Vm) of their polarity with respect to the resting Vm.
The relation between EGABA and Vm of hippocampal interneurons is of particular interest. GABA-mediated membrane currents in hippocampal neurons may be depolarizing in young animals (Mueller et al., 1984
MATERIALS AND METHODS Hippocampal slice preparation. Rats aged between 1 and 21 d were anesthetized by intraperitoneal injection of a ketamine-chloral hydrate solution (5 and 18%, respectively; 1 ml/200 gm). Under deep anesthesia, the vascular system was perfused through the heart with an ice-cold low Ca2+ solution containing (in mM): 130 NaCl, 2.7 KCl, 20 NaHCO3, 0.4 CaCl2, 1 MgCl2, 1.3 NaH2PO4, and 25 glucose, equilibrated with 5% CO2 and 95% O2. After perfusion, the brain was removed, and sagittal slices of 200-300 µM were cut from the middle third of the hippocampus using a vibratome (DTK-1000 microslicer; Dosaka, Kyoto, Japan). Slices were allowed to recover for at least 1 hr in the above solution with 2 mM CaCl2 ("extracellular solution"). For recordings, slices were placed in a chamber mounted on the stage of a microscope (Nikon Optiphot with a 40×, 0.55 NA objective). They were held in place by a nylon grid and continuously superfused with the oxygenated extracellular solution at room temperature (24-26°C).
Cell-attached and whole-cell patch-clamp recording. Hippocampal interneurons in stratum radiatum of the CA1 area were visualized using a CCD camera (Hamamatsu C3077) with light filtered to pass visible and infrared. Pipettes (Clark Electromedical Instruments, Pangbourne, UK; GC150 borosilicate glass) with a resistance of 2-6 M
were filled with a high K+ solution consisting of (in mM): 120 KCl, 11 EGTA, 1 CaCl2, 2 MgCl2, 10 HEPES, adjusted to pH 7.25 with 35 mM KOH (final K+ concentration 155 mM) and to 310 mOsmol with 20 glucose, unless stated otherwise. The junction potential between pipette and extracellular solution (<3 mV as measured according to Neher, 1992
Using the reversal potential of K+ currents through cell-attached patches as a monitor of the membrane potential. The method to measure Vm from cell-attached K+ currents was adapted from Verheugen et al. (1995)
0 mV). With this approach, differences between intracellular and pipette K+ concentration would result in errors in the Vm estimate, which will be too negative when [K+]i < [K+]pipette. However, with a [K+]pipette of 155 mM a difference of, for example, 15 mM would result in an error of RT/F · ln(155/140) < 3 mV. Depolarizing voltage ramps (from Vh =
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Figure 1. Voltage-gated K+ currents measured in cell-attached patches of CA1 interneurons. A shows currents activated by applying depolarizing voltage steps, and B shows the response to a voltage ramp applied to the same cell, with a pipette solution containing 155 mM K+. A, The inward K+ current caused the generation of action currents in this cell (Lynch and Barry, 1989
Pharmacology. GABA, muscimol, baclofen, and TTX (all from Sigma, St. Louis, MO) and NBQX and APV (Tocris, Bristol, UK) were made up as 1000× concentrated stocks and diluted to their final concentrations in the external solution before use. The compounds were applied via bath perfusion. Using a gravity-driven perfusion system, the bath solution completely changed in ~30 sec.
RESULTS Vm measurements from cell-attached K(V) currents
The membrane potential of interneurons in the stratum radiatum of the CA1 area of hippocampal slices was estimated from the reversal potential of voltage-gated K+ currents activated by command potentials applied via a cell-attached pipette (Fig. 1). This technique permits control of the timing of measurements and is more precise than estimates from changes in amplitude of spontaneous K+ channel open events (Zhang and Jackson, 1993
Voltage ramp stimulation produced similar I-V relations to those derived from responses to current steps (Fig. 1B). The currents were selective for K+ because they were outward over the entire voltage range with pipettes containing low K+ (20 mM; Fig. 1C). Furthermore, there were no differences in depolarization evoked currents when the pipette solution contained Cl
Ramp stimuli were routinely used to determine the K(V) current reversal potential and hence Vm. A correction was made for the linear leak current evident at potentials below the K(V) current threshold (Fig. 1, dotted lines). Short duration (15-20 msec) ramps were preferred because they minimized transmembrane charge flux while still producing close to maximal activation of the K(V) current (Figs. 2-5). Ramp stimuli could be repeated at frequencies up to 1 Hz without significant accumulation of use-dependent K+ current inactivation. The mean resting Vm of CA1 interneurons, estimated with the cell-attached approach, was
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Figure 2. Differences between cell-attached and whole-cell Vm measurements. A, Determination of K+ current reversal, and hence membrane potential, from a CA1 interneuron after exposure to high external [K+] and to GABA (50 µM). This cell discharged spontaneously, giving rise to action currents visible in the cell-attached record (arrows). For each condition, five consecutive current traces recorded at 2 sec intervals are shown. Bottom panels show the inward K(V) and its reversal in greater detail. B, Plot of Vm determinations (circles; for each condition average Vm and SD are indicated by solid and dotted lines, respectively) and the mean firing frequency (shaded bar) in the presence of high K+ and GABA. Increasingextracellular [K+] from 2.5 to 10.5 mM caused a depolarization, and the firing rate increased. In contrast, during GABA application Vm stabilized, and the generation of action currents ceased. C, Vm measured subsequently from the same cell in the whole-cell current-clamp mode was more depolarized. No spontaneous AP activity was seen, and membrane potential was stable within 2-3 mV. Increasing [K+]o and GABA application both strongly excited the cell. The pipette solution contained 120 mM Cl
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Figure 3. The Donnan potential between cytoplasm and pipette in the whole-cell mode can account for the difference in cell-attached and current-clamp Vm estimates. A, Three superimposed cell-attached current traces from a cell with spontaneous single-channel activity (K"ATP"). Two independent estimates for Vm can be obtained from these records. With the single-channel amplitude at Vh =
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Figure 4. Effects of GABA receptor activation on the Vm of intact CA1 interneurons. Vm of two CA1 interneurons under control conditions and in the presence of bath-applied GABA and TTX (A) and GABA and NBQX/APV (B) monitored from the cell-attached K(V) current reversal. Vm of both interneurons fluctuated spontaneously, which was associated with AP activity (see current trace in A). The fluctuations were largely suppressed by TTX (0.5 µM; A) or by NBQX/APV (20 and 100 µM; B), indicating that they arise from excitatory input to the cell, although the AHPs after action potentials contribute to the hyperpolarizing deflections (A, asterisks). The principal effect of bath-applied GABA in P7-P21 animals is a stabilization of the Vm, usually at a level that is not significantly different (A) or slightly depolarized (B) from the average control level. The inset shows for each condition the reversal of K(V) currents from 10 consecutive cell-attached responses to ramp stimuli applied at 2 sec intervals. C, Summary of GABA effects on interneurons from P7-P21 (left) and P1-P4 rats (right). In the older animals, GABA caused Vm to stabilize at a potential close to control level, whereas in young animals it induced a membrane depolarization. Cells are aligned according to the average Vm. Minimum and maximum Vm levels are indicated in the presence and absence of GABA. The mean Vm of cells in the two age groups was not significantly different (p > 0.1). The black circles under the graph indicate the approximate age of the animal, with each postnatal week corresponding to one circle; an empty half circle indicates 1-to 2-d-old rats. Cells originating from the same animal are identified with symbols.
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Figure 5. Age dependence of the effects of activating GABAA and GABAB receptors. Each experiment shows membrane potential responses to application of GABA (50 µM), to activation of GABAB receptors by baclofen (50 µM), and to the activation of GABAA receptors by muscimol (50 µM). A, B, In animals older than P7, activation of GABAA receptors induced a depolarizing response, whereas GABAB receptor activation induced a hyperpolarization. The effects of GABA were a balance depending on combined responses of both receptor subtypes. C, In interneurons from young (P1-P4) animals, GABAB receptor activation had no effect, and both GABA and muscimol induced depolarizing responses.
Large fluctuations in Vm, with an amplitude of 21 ± 6 mV, were apparent in a subset of the cells (n = 22 cells). Action currents were usually visible in the cell-attached records from these neurons (Fig. 2A). The afterhyperpolarizations after the action potentials (APs) (which may be of large amplitudes in CA1 interneurons; Parra et al., 1998
To compare measurements of Vm from K+ current reversal in cell-attached records with those determined using the traditional whole-cell current-clamp configuration, the two methods were applied sequentially in experiments on 21 cells. Several differences between the two approaches were apparent (Fig. 2C).
First, values for membrane potential were systematically different. With a high Cl
Of note, the observation that intracellular perfusion with a high Cl
Origin of the difference in cell-attached and whole-cell Vm estimates
Two possible explanations were considered to explain the difference in cell-attached and whole-cell estimates for Vm. First, it could result from an artifactual shift in Vm induced by the ramp stimulation in cell-attached recordings. Determinations of Vm made using a second independent method based on spontaneous single K+ channel openings seem to exclude this explanation.
In some patches, spontaneous openings of non-voltage-activated K+ channels were apparent in addition to the K(V) current gated by membrane depolarization. Figure 3A shows spontaneous activity of a channel with conductance and inward rectification properties similar to those of an ATP-sensitive K+ channel described in cortical cells (Ohno-Shosaku and Yamamoto, 1992
A second explanation for the difference between cell-attached and whole-cell measurements of Vm might be the existence of a Donnan potential between the pipette solution and the cytoplasm. Such a potential would lead to an underestimation of the Vm in whole-cell experiments (Barry and Lynch, 1991
Effects of GABAergic agonists on Vm in intact interneurons
During experiments to examine Donnan shifts in voltage dependence of K+ currents, a partial rundown of the peak current was usually apparent (Fig. 3C). In contrast, the K(V) current never ran down in the cell-attached mode. This difference presumably reflects the better conservation of the cytoplasmic environment in cell-attached recordings. Cell-attached measurements of Vm might therefore offer significant advantages in studies on neurotransmitters whose actions depend critically on the cytoplasmic contents. One such neurotransmitter is GABA, which opens Cl
Exogenous GABA (50 µM) and the selective GABAA and GABAB agonists muscimol (50 µM) and baclofen (50 µM) were applied by bath perfusion while monitoring Vm from the reversal of cell-attached K+ currents (Fig. 4). Because GABAergic actions on pyramidal cells are reported to change with age (in rabbit: Mueller et al., 1984
In the older age group, GABA hyperpolarized a small minority of the interneurons (5%; n = 39). More cells (26%) depolarized in the presence of GABA (Fig. 4B). However, in the vast majority of the cells (69%), no significant change in the average level of Vm occurred (Fig. 4A). These qualitatively different responses to GABA could be observed in interneurons derived from the same animal (Fig. 4C). Irrespective of the change in average Vm, GABA tended to stabilize interneuron membrane potential (Fig. 4A,B; see also Fig. 2). This effect was particularly striking in cells with strong Vm fluctuations and spontaneous firing activity, which invariably ceased in the presence of GABA (Figs. 2, 4C).
As described above, these membrane potential fluctuations were usually associated with action current generation and, as expected, were considerably reduced in the presence of a 0.5 µM concentration of the Na(V) channel blocker TTX (Fig. 4A). It seems probable that action potential generation by these interneurons was largely dependent on excitatory synaptic inputs because exposure to the excitatory amino acid antagonists NBQX (20 µM) and APV (100 µM) also significantly reduced membrane potential fluctuations (Fig. 4B). These data suggest therefore that the primary effect of simultaneous strong activation of both GABAA and GABAB receptors is to stabilize Vm of interneurons from P7-P21 rats, presumably by a shunting action.
In contrast to the relatively small effects on the average level of Vm in older animals, GABA invariably depolarized interneurons from animals aged between 1 and 4 d (Figs. 4C, 5C). In young animals its effect in stabilizing fluctuations in Vm was much less pronounced (Fig. 4C). However, in young animals, as in old, depolarizations induced by GABA rarely caused an excitation. Only in one of seven P1-P4 cells, the depolarization induced by GABA was sufficient to evoke APs.
The contribution of different subtypes of GABA receptors was examined by comparing the effects on Vm of GABA (50 µM), muscimol (50 µM) to activate GABAA receptors, and baclofen (50 µM) to activate GABAB receptors (Fig. 5). These experiments revealed that responses to GABA depended on the balance between contributions of the GABAA-activated Cl
Whereas GABA and muscimol had different effects on Vm in P7-P21 rats, in interneurons from young animals these two agonists caused similar depolarizations, to
DISCUSSION Measurements of neuronal membrane potential and neurotransmitter actions are more difficult than commonly admitted. We have shown that the reversal of voltage-gated K+ currents elicited in cell-attached patches can provide a noninvasive way to determine these parameters. This technique has several advantages: (1) it provides a local measure of Vm, at the site of the patch; (2) it does not disrupt the cytoplasmic environment; and (3) it avoids Donnan junction potential problems. In this study we validated the technique and used it to examine GABA actions on hippocampal interneurons.
Validation of the technique
Variations in amplitude of cell-attached currents passing through single potassium channels have previously been used to infer changes in Vm in neurons in response to GABA (Zhang and Jackson, 1993
One potential problem is that the ion current through the K(V) channels could result in a change of Vm (Fig. 1A). However, because the patch current is, by definition, zero at the reversal potential, this point should be accurate. The use of fast voltage ramps to determine K(V) reversal further reduces transmembrane charge fluxes. Similar values for Vm estimates from macroscopic and single-channel currents (Fig. 3A) provide additional evidence that under the present conditions the cell-attached currents had little influence on Vm.
Another potential source of error might be a mismatch between the [K+] used in our pipette solution and the effective cytoplasmic [K+]. Deviations from symmetrical K+ would result in an EK across the patch different from 0 mV. However, based on the Nernst equation we calculate that an error of for instance 15 mM in the choice of pipette [K+] would result in a systematic error of only 3 mV in our determinations of Vm.
The Vm values obtained from the cell-attached K(V) reversal were on average 15 mV more negative than those measured subsequently in whole-cell current-clamp recordings in the same neuron. The existence of a Donnan potential between the cytoplasm and pipette solution immediately after break-in to the whole-cell mode probably accounts for this difference. During the first 5-20 min after the whole-cell configuration was established, the voltage dependence of voltage-gated currents shifted by a similar value (Fig. 3C) most likely corresponding to equilibration between the cytoplasm and the recording pipette and consequent dissipation of the Donnan potential (Marty and Neher, 1995
Another advantage of this technique is that the cytoplasmic environment is preserved. In contrast, in the whole-cell technique the pipette solution controls over time the intracellular content, disturbing physiological ion gradients and diluting intracellular factors. The perforated patch technique, which uses antibiotics to render cell membranes permeant to monovalent ions (e.g., nystatin; Horn and Marty, 1988
Measurements of GABA actions on hippocampal interneurons
Actions of the neurotransmitter GABA depend crucially on the intracellular activities of Cl
We found that bath-applied GABA stabilized the Vm of interneurons at a level similar to its control value in slices from animals aged 1-3 weeks. Dissection of this response using selective agonists suggested that the membrane stabilization represented a balance between a hyperpolarizing action via GABAB receptors and a depolarization mediated by GABAA receptor activation. In contrast, in animals aged 1-4 d, the GABAB receptor agonist baclofen had no effect, as observed also in CA3 pyramidal cells at a similar developmental stage (Strata and Cherubini, 1994
The origin of depolarizing responses to GABAA receptor activation remains to be completely understood. In this study, muscimol depolarized CA1 interneurons to similar membrane potentials, close to
The observation that muscimol depolarizes Vm of CA1 interneurons in young and old animals to exactly the same level could suggest that the Cl
In this study we assessed the effects of GABA receptor activation on Vm from the reversal of somatic K+ fluxes. This approach yields a point potential at the somatic patch, which may differ from that at other membrane surface sites (Spruston and Johnston, 1992
FOOTNOTES Received Nov. 30, 1998; revised Jan. 21, 1999; accepted Jan. 25, 1999.
This work was supported by the Human Frontiers Science Organization, the National Institutes of Health (MH54671), and Institut National de la Santé et de la Recherche Médicale. We thank I. Cohen for writing the data analysis program.
Correspondence should be addressed to Dr. Jos A. H. Verheugen, Laboratoire de Neurobiologie Cellulaire et Moleculaire, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France.
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