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Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark
Submitted 12 June 2006; accepted in final form 3 August 2006
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ABSTRACT |
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INTRODUCTION |
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); they contribute to the left–right coordination of the body (Butt and Kiehn 2003; Butt et al. 2002; Jankowska and Noga 1990; Stein et al. 1995; Stokke et al. 2002); and are active during rhythmic movements such as locomotion (Butt and Kiehn 2003; Kjærulff and Kiehn 1996; Pratt and Jordan 1987), swimming (Grillner 2003; Sillar and Roberts 1993), or scratching (Berkowitz 2005).
Three fundamentally different approaches have been used to categorize spinal neurons. The traditional way is to determine the nature of primary afferents contacting neurons (Baldissera et al. 1981; Jankowska 1992). A more recent approach consists in identifying functional subclasses of neurons according to the homeodomain transcription factors they express (Jessel 2000; Lanuza et al. 2004; Wilson et al. 2005). A third method is based on the determination of intrinsic properties expressed by individual spinal neurons (Hounsgaard and Kjærulff 1992; Morisset and Nagy 1999; Murase and Randic 1983; Russo and Hounsgaard 1996a,b; Yoshimura and Jessell 1989). This approach is physiologically relevant because, together with synaptic inputs, currents mediated by voltage-gated ion channels determine the precise timing of action potentials in individual neurons (Llinas 1988). Moreover, the behavior of small neuronal networks is dictated by the intrinsic properties of individual cells in combination with the properties of synaptic connections and the pattern of interconnections between nerve cells (Arshavsky 2003; Marder and Calabrese 1996; Stein et al. 1997).
Only a few studies performed in preparations from embryonic or neonatal animals have investigated the intrinsic properties from ventral horn interneurons (Butt and Kiehn 2003; Butt et al. 2002; Szucs et al. 2003; Theiss and Heckman 2005; Wilson et al. 2005). However, the motor repertoire of neonates is quite poor compared with that from adult animals. The increase in complexity of motor behaviors that occurs throughout development is correlated with dramatic changes in the nature and variety of ion channels expressed in neuronal membranes (Furlan et al. 2005; Gao and Ziskind-Conhaim 1998; Huang et al. 2006; Jiang et al. 1999; Martin-Carballo and Greer 2000; Perrier and Hounsgaard 2000; Song et al. 2006; Spitzer and Ribera 1998; Vinay et al. 2000). For this reason, the contribution of intrinsic properties to the function of mature spinal motor network ought to be established in adult vertebrates. In the absence of a slice preparation from an adult mammal in which ventral horn interneurons remain viable these studies have not yet been performed.
Here we have used the spinal cord of the adult turtle because of its high resistance to anoxia. Using the whole cell blind patch-clamp technique, we examined the intrinsic properties of ventral horn interneurons. We show that ventral horn interneurons display a broad variety of discharge patterns produced by different intrinsic properties.
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METHODS |
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Experiments were performed in vitro on transverse slices (1.5 mm thick) from the spinal cord lumbar enlargement (D8–S2) from the adult turtle (Chrysemys scripta elegans). The turtles were anesthetized by intraperitoneal injection of 100 mg sodium pentobarbitone and killed by decapitation. The surgical procedures complied with Danish legislation and were approved by the controlling body under The Ministry of Justice. Experiments were performed at room temperature (20–22°C) in a solution containing (in mM): 120 NaCl, 5 KCl, 15 NaHCO3, 2 MgCl2, 3 CaCl2, and 20 glucose, saturated with 98% O2-2% CO2 to obtain pH 7.6.
Electrophysiological recordings
Whole cell blind patch-clamp recordings of ventral horn interneurons were performed with borosilicate pipettes filled with Mg-gluconate (1.53 mM), MgCl2 (3.7 mM), CaCl2 (300 nM), HEPES (5 mM), Na-HEPES (5 mM), Na2ATP (2 mM), K-CH3SO4 (127 mM), and biocytin (10 mM). The pipette resistance was typically 5–10 M
when measured in the bath. Current-clamp recordings were performed either with an Axoclamp 2A, an Axoclamp 2B, or a Multiclamp 700B amplifier (Molecular Devices, Sunnyvale, CA). Data were collected and analyzed by means of pCLAMP software (Molecular Devices), sampled at 10–20 kHz with a 12- or 16-bit A/D converter (Digidata 1200 or Digidata 1322A; Molecular Devices), and stored on a hard disk for later analysis. Membrane potential values were not corrected for liquid junction potential.
Staining procedure
Cells were injected with biocytin (10 mM, Sigma) using 500-ms depolarizing pulses of current at 1 Hz (10–100 pA). Slices were immersed in 4% paraformadehyde overnight and rinsed three times in PBS. Sections (50–100 µm) were made with a vibratome or a cryostat. Slices, incubated with streptavidin conjugated with Alexa 488 (Molecular Probes) together with Triton-X (0.3%) and 0.2% fish gelatin, were then mounted on objective glass with antifade medium Prolong gold or Prolong antifade Kit (Molecular Probes). Neurons were visualized with a confocal microscope (Leica TCS SP2). The location of soma was normalized to the position of the central canal and the most lateral point of the ventral horn by dragging a snapshot to a standard drawing of the spinal cord. Because of the lack of laminar organization in the spinal cord of the turtle (Fernandez et al. 1993; Trujillo-Cenoz et al. 1990), we did not refer to the laminae numbers defined by Rexed for mammals.
Drugs
Fast synaptic inputs were eliminated by a mixture of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 25 µM; Tocris), D-2-amino-5-phosphonopentanoic acid (D-AP5, 50 µM; Tocris), (+)-bicuculline (20 µM; Tocris), and strychnine (10 µM) added to the extracellular medium. Other drugs used were ZD7288 (100 µM; Sigma), nifedipine (10 µM; Sigma), 4-aminopyridine (4-AP; 4–5 mM; Merck, Darmstadt, Germany), and tetrodotoxin (TTX; 1 µM; Alomone Labs, Jerusalem, Israel).
Data quantification
The input resistance of recorded cells was estimated as the voltage change induced by small hyperpolarizing current pulses (–10 to –100 pA) applied from –60 to –65 mV. The rheobase was calculated as the amount of current necessary to generate one action potential. For cells firing at rest (n = 66), a negative bias current was injected to hold the membrane potential at –70 mV. The rheobase was then estimated from this value.
Firing patterns were characterized during 2-s depolarizing current pulses of twice the rheobase value. A firing pattern index (FPI) was defined as the difference between the mean frequency of action potentials occurring during the last 500 ms (ML) and the first 500 ms (MF) of the current pulse divided by the mean frequency during the whole pulse (MW)
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Data were analyzed statistically by using two populations (paired or independent when appropriate) t-test (OriginPro 7.5; OriginLab, Northampton, MA). Significance was accepted when P < 0.05. Data are presented as means ± SD.
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RESULTS |
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(mean = 560 ± 489 M; n = 187; Fig. 1A). Neurons that were not firing at rest had a mean membrane potential of –58.4 ± 5.9 mV; n = 97). The size of cell bodies recovered from recorded stained neurons (n = 42) ranged from 11.5 to 51 µm (long diameter; mean: 23.1 ± 7.7 µm; Fig. 1D) or from 7.8 to 29 µm (short diameter; mean: 12.9 ± 3.8 µm; Fig. 1C). These values are significantly lower than the mean diameters of turtle motoneurons reported in other studies (40 ± 9.7 µm; P < 0.01; McDonagh et al. 2002). The somas were located in the intermediate zone or in the ventral horn, dorsally to the motor columns (Fig. 1B). The cells from which we recorded were located 22–404 µm (mean 145 ± 95 µm) from the surface of the slice. Each of them had between 1 and 5 primary dendrites (mean 2.6 ± 1.1) with a length ranging from 37 to 737 µm (mean: 167 ± 162 µm). All the interneurons had dendrites projecting in the transversal plan (n = 42); 16 of these neurons had one or more dendrites projecting in the rostrocaudal direction.
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We characterized the firing pattern of ventral horn interneurons by calculating two indices. First, we calculated the slope of a linear regression of the instantaneous frequency of action potentials during 2-s depolarizing current pulses at twice the rheobase value (55 of the 207 neurons were tested). For 19 cells (35%) the slope value was below –1, indicating a degree of adaptation of the firing frequency. For 21 neurons (38%), the frequency of action potentials did not significantly change because the slope ranged from –1 to 1. For the last 15 cells (27%), the slope was >1, demonstrating an increasing firing frequency.
To refine the categorization of firing patterns, we determined a firing pattern index (FPI) from the response to 2-s depolarizing current pulses at twice the rheobase value (see METHODS). Of the 207 interneurons, 56 were tested in this way. Of the 56 cells tested, nine (16%) had a bursting firing pattern (Fig. 2A) with a spike frequency decay of >30% (FPI < –0.3); five of these cells were firing at rest. The others had a resting potential of –59.7 ± 3.3 mV. Twelve cells (21%) had an FPI value between –0.3 and –0.1 and were therefore categorized as adaptation (Fig. 2B). Nine cells (16%) had a firing frequency within ±10% of the mean value (–0.1 < FPI < 0.1). Such a firing pattern was considered regular (Fig. 2C). All other interneurons tested (n = 26; 47%) displayed incremental firing because they responded with an increased spike frequency of >10% (Fig. 2D; FPI > 0.1). The distribution of the different categories of FPI index is summarized in Fig. 2E.
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Plateau properties
The most common firing pattern observed during depolarizing current pulses was an acceleration of the firing frequency (Fig. 2D; n = 76 of 166, i.e., 46%; this number includes cells that were not tested at twice the rheobase value). Action potentials generated during 2-s depolarizing current pulses were either followed by an afterhyperpolarization (n = 22/76; Fig. 3A), or by and afterdepolarization that could be sufficient to trigger action potentials (Fig. 3B; n = 54/76). Depolarizing pulses could also trigger a bistable firing pattern (Fig. 3C1; n = 32). Figure 3C1 illustrates an interneuron that was kept silent with a negative bias current. A depolarizing current pulse to 0 pA generated action potentials with an accelerating frequency and triggered firing that continued for seconds after the current pulse was turned off. The bistable firing could be terminated with a negative current pulse (Fig. 3C2). This example demonstrates that plateau potentials contributed to the resting membrane potential of some interneurons (n = 12). Extracellular addition of nifedipine (10 µM) blocked the acceleration in spike generation during the current pulse as well as the afterdischarge (Fig. 3D; n = 6/6), suggesting that both were mediated by L-type calcium channels.
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We observed delayed firing in 14% of the interneurons tested at twice the rheobase (Fig. 2F). In the presence of blockers for fast synaptic transmission (see METHODS), we studied the voltage sensitivity of the delay. We found that depolarizing current pulses after a hyperpolarizing current pulse generated a voltage-sensitive transient hyperpolarization that postponed the occurrence of the first action potential (n = 36 of 163 neurons tested; i.e., 22%; Fig. 4, A and C). In a few instances, however, when the depolarizing current pulse reached a sufficient level, an action potential was generated before the transient hyperpolarization (n = 8/36; Fig. 4F). This could be a result of the interaction between a postinhibitory rebound (see following text) and the transient hyperpolarization. The amplitude of the negative transient induced by depolarizations was sensitive to the amplitude of the preceding negative current pulse (Fig. 4, B and C; n = 19/19). The negative transient disappeared in the presence of 4-aminopyridine (4–5 mM; Fig. 4E; n = 10/10). These results demonstrate that a voltage-sensitive transient outward rectifying conductance delays the firing in a sizeable fraction of interneurons.
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Sixteen percent of the interneurons responded to depolarizing pulses of twice the rheobase value by a bursting firing pattern (Fig. 2A). We tested whether this pattern was mediated by a postinhibitory rebound (PIR). We recorded the response of interneurons to hyperpolarizing current pulses of increasing amplitudes. For the vast majority of the cells from which we recorded (n = 156 of 181; i.e., 86%), current pulses induced a depolarizing sag with an amplitude that increased linearly with the level of hyperpolarization (Fig. 5, A and B; threshold for the sag –71.9 ± 6.4 mV). In most cases, when the current pulse was turned off, the sag was followed by a PIR (n = 133 of 151 cells tested, i.e., 88%) that could reach the threshold for action potentials (Fig. 5A). The threshold for the PIR, estimated with an activation protocol similar to that used for characterizing the transient outward rectification (Fig. 4A), ranged from –53 to –85 mV (mean value: –70.2 ± 7.5 mV), which was not significantly different from the threshold for the depolarizing sag (P > 0.05; paired t-test). The threshold for the PIR overlapped with the resting membrane potential (ranging from –44 to –75 mV), indicating that, at least in some instances, PIRs were evoked by depolarizing current pulses applied from resting membrane potential. In support of this hypothesis, we found that a hyperpolarizing current pulse, applied from a positive level to 0 pA, evoked a depolarizing sag (Fig. 5, C and D; n = 10 of 21 cells tested). Both the sag and the PIR were sensitive to ZD7288 (100 µM; n = 17; Fig. 5, E and F), suggesting that they were mediated by a hyperpolarization-activated inward cationic current (Ih).
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We showed above that different intrinsic properties (plateau potential, transient outward rectification, slow inward rectification, and low-threshold spikes) control the firing pattern of ventral horn interneurons. These properties were usually not expressed alone but in different combinations. To estimate the occurrence of these combinations, we systematically tested the presence of the four intrinsic properties (n = 135). We first estimated the incidence of cells expressing two properties together. With the exception of LTS and transient outward rectification that were never expressed together, we found all the possible pairs of properties (results summarized in Table 1). We also looked for neurons expressing three properties together and found 14 interneurons out of 135 (10%) in which the transient outward rectification, plateau properties, and slow inward rectification were coexpressed and three cells (2%) that coexpressed LTS, plateau properties, and slow inward rectification. Because LTS and transient outward rectification were never recorded in the same neuron, none of the interneurons expressed all four properties.
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DISCUSSION |
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Sample of ventral horn interneurons
Previous work investigated the firing patterns of ventral horn interneurons from the adult turtle (Berkowitz 2005; Berkowitz et al. 2006; Hounsgaard and Kjærulff 1992). In these studies, interneurons were recorded by means of sharp electrodes. This technique allows the recording of the biggest interneurons. By comparison, whole cell patch-clamp recording gives access to much smaller cells. In support of this assertion, we found that the mean input resistance of the interneurons from our sample was higher than that reported by Hounsgaard and Kjærulff (560 vs. 130 M). However, we cannot rule out that the high-input resistance of the cells in our sample also arises from the absence of shunting with patch recording technique, washout of leak conductance, or amputation of dendritic trees in the slices. To compare more directly the sizes of cells recorded with sharp and patch electrodes, we measured the diameter of the 12 ventral horn interneurons recorded with sharp electrodes and illustrated in Berkowitz (2005) and Berkowitz et al. (2006). Their diameter was significantly larger (long: 30.6 ± 10.8 µm; short: 16.9 ± 5.5) compared with the interneurons from our sample (independent t-test; P < 0.01 both for the long and the short diameter). These differences strongly suggest that our sample of interneurons contains cell types that have not been recorded before.
The broad diversity of firing patterns is specific to adult interneurons
Few studies have investigated the nature of intrinsic properties present in interneurons from the ventral horn of neonatal or embryonic animals (Butt and Kiehn 2003; Butt et al. 2002; Szucs et al. 2003; Theiss and Heckman 2005; Wilson et al. 2005). These studies reported firing patterns including single-spike firing (Szucs et al. 2003; Theiss and Heckman 2005), repetitive firing (Szucs et al. 2003; Theiss and Heckman 2005), and bursting firing (Theiss and Heckman 2005; Wilson et al. 2005). In our study, all the interneurons were able to fire repetitively. This observation suggests that single-spike firing is a transient behavior occurring only during development, as is the case for motoneurons (Gao and Ziskind-Conhaim 1998; Vinay et al. 2000). In addition to repetitive and bursting firing, we found that ventral horn interneurons from the adult turtle have accelerating, delayed, and oscillatory firing patterns (Fig. 2). To the best of our knowledge, none of these latter behaviors was previously reported in neonatal or embryonic spinal interneurons. In the absence of intrinsic properties, interneurons would fire at a constant rate as is the case in the majority of ventral horn neurons from the spinal cord of neonatal rats (Szucs et al. 2003; Theiss and Heckman 2005). Here we found that only 16% on the ventral horn interneurons displayed such a regular firing pattern. These differences indicate that intrinsic properties from ventral horn interneurons are altered during development.
Intrinsic properties determine the firing patterns of interneurons
The vast majority of interneurons (86%) expressed a slow inward rectification property. It was characterized by a slowly activating depolarizing sag appearing on hyperpolarization and a postinhibitory rebound (PIR) on return to initial membrane potential. Because both were blocked by ZD7288, they were probably mediated by an Ih current (Robinson and Siegelbaum 2003). Ih was active at resting membrane potential in 48% of neurons. For these neurons, a depolarizing pulse applied from resting membrane potential induced an extra depolarization resulting from the relaxation of Ih (Fig. 5, C and D). Because the PIR can trigger action potentials, Ih may contribute to the adaptation of spike frequency during depolarizing current pulses. Other mechanisms such as the increase of the afterhyperhyperpolarization arising from calcium accumulation (Yarom et al. 1985), the activation of an M-current (Alaburda et al. 2002a), or the slow inactivation of the fast, inactivating Na+ conductance (Miles et al. 2005) may also contribute to the adaptation of action potential frequency.
We ascribed the accelerating firing pattern observed in 47% of the interneurons in response to depolarizing current pulses at twice the rheobase value (Fig. 2D) to a plateau potential mediated by L-type calcium channels. Our assumption is based on the fact that the acceleration of the spike frequency as well as the afterdepolarization present after the current pulse injection disappeared in the presence of nifedipine. This result is in agreement with previous observations made in ventral horn intereurons (Hounsgaard and Kjærulff 1992), deep dorsal interneurons (Russo and Hounsgaard 1996a), or motoneurons (Hounsgaard and Mintz 1988; Simon et al. 2003). However, we cannot rule out that other conductances such as a persistent sodium current (Li and Bennett 2003) or a calcium-activated nonselective cationic current (Morisset and Nagy 1999; but see Perrier and Hounsgaard 1999) contributed to plateau properties.
The voltage-sensitive transient outward rectification recorded in 22% of the interneurons generates a transient hyperpolarization that delays the occurrence of action potentials generated by depolarizing current pulses (Fig. 4). It was activated by depolarization after hyperpolarization, had a threshold close to that for action potentials, and was sensitive to 4-aminopyridine. Taken together, these results suggest that the transient outward rectification was mediated by a low-voltage–activated A-current (Rogawski 1985). However, we cannot rule out the contribution of a D-current (Storm 1988). In some instances, a delayed firing was not present when tested with a depolarizing current pulse from –70 mV, but was detected when the depolarization was preceded by a transient hyperpolarization. This explains why we observed a delayed firing in only 14% of the interneurons and a transient outward rectification in 22% of them.
We found that burst firing arising from a postinhibitory rebound can be mediated either by slow inward rectification or by a low-threshold spike (LTS). The LTS was induced by depolarization after hyperpolarization in an all-or-none manner. It had a low threshold (–58 mV) and was insensitive to TTX. Although we did not demonstrate it, these results are compatible with a spike mediated by a T-type calcium current, as the one recorded in deep dorsal horn neurons of the turtle (Russo and Hounsgaard 1996b) or in ventral horn interneurons of the neonatal mouse (Wilson et al. 2005).
We recorded four interneurons with oscillatory behaviors. Two arguments suggest that they were mediated by intrinsic properties. First, the oscillations persisted when fast synaptic transmission was blocked; and second, the frequency of oscillations was voltage sensitive. Oscillations of the membrane potential promoted by metabotropic modulation were previously recorded in deep dorsal horn interneurons of the neonatal rat (Derjean et al. 2003). Here we show that oscillations also occur in ventral horn interneurons, even in the absence of pharmacological activation.
Functional considerations
We recorded plateau potentials and bistable firing in interneurons at resting membrane potential and in the absence of metabotropic modulation. This observation contrasts with that of spinal motoneurons, in which plateau potentials are not expressed in the absence of neuromodulation (Alaburda et al. 2002b; Perrier et al. 2002). This suggests that plateau potentials from ventral horn interneurons may participate in tonic firing in interneurons and thereby contribute to the background activity of the spinal network.
A major function of the spinal motor network is to generate rhythmic activity such as locomotion (Graham-Brown 1911). It is not known whether the activity of the spinal network depends on intrinsic properties of interneurons, as in networks from invertebrates (Arshavsky 2003), or whether it is an emergent property originating from synaptic interactions between neurons in the network. Recent works have provided evidence for (Paton et al. 2006; Pena et al. 2004) and against (Alaburda et al. 2005; Del Negro et al. 2002) the contribution of intrinsic properties to network activity. An alternative possibility would be that rhythmic activity results from a combination of these two mechanisms. In the present study, we found that a small fraction of ventral horn interneurons displayed intrinsic oscillation properties. Despite lack of evidence, it is tempting to link this observation to the global activity generated by the spinal network during rhythmic activities.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: J.-F. Perrier; MFI, Panum Institute; Blegdamsvej 3, DK-2200 Denmark (E-mail: perrier{at}mfi.ku.dk)
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